ip3
IP3_百度百科
百度百科 網(wǎng)頁新聞貼吧知道網(wǎng)盤圖片視頻地圖文庫資訊采購百科百度首頁登錄注冊(cè)進(jìn)入詞條全站搜索幫助首頁秒懂百科特色百科知識(shí)專題加入百科百科團(tuán)隊(duì)權(quán)威合作下載百科APP個(gè)人中心IP3播報(bào)討論上傳視頻三磷酸肌醇收藏查看我的收藏0有用+10IP?（inositol triphosphate，三磷酸肌醇），參與G蛋白耦聯(lián)受體介導(dǎo)的信號(hào)轉(zhuǎn)導(dǎo)的第二信使。在磷脂酰肌醇途徑中，胞外信號(hào)分子與其相應(yīng)的G蛋白偶聯(lián)受體結(jié)合后，激活膜上的Gq蛋白（一種作用于磷脂酰肌醇系統(tǒng)的G蛋白），然后由Gp蛋白激活磷酸酯酶Cβ （phospholipase Cβ，PLC）， 將膜上的4，5-二磷酸脂酰肌醇（phosphatidylinositol biphosphate， PIP2）分解為兩個(gè)細(xì)胞內(nèi)的第二信使： DAG和IP?，最后通過激活蛋白激酶C（protein kinase C，PKC），引起級(jí)聯(lián)反應(yīng)，進(jìn)行細(xì)胞的應(yīng)答。該通路也稱IP?、DAG、Ca2+信號(hào)通路。中文名三磷酸肌醇外文名inositol 1,4,5-trisphosphate, IP3水溶性可溶性????質(zhì)可以從質(zhì)膜擴(kuò)散到胞質(zhì)溶膠分子量420.10分子式C6H15O15P3目錄1簡介2化學(xué)性質(zhì)3信號(hào)通路4功能5相關(guān)疾病?亨廷頓病?阿爾茨海默病簡介播報(bào)編輯肌醇三磷酸（IP3）是一種肌醇磷酸信號(hào)分子。它是通過磷脂酶C（PLC）水解位于細(xì)胞膜中的磷脂酰肌醇-4,5-二磷酸（PIP2）而產(chǎn)生的。與二?；视停―AG）一樣，IP3是生物細(xì)胞信號(hào)轉(zhuǎn)導(dǎo)中使用的第二信使分子。但與DAG留在膜內(nèi)不同，IP3是可溶的，并在細(xì)胞內(nèi)擴(kuò)散，與其受體結(jié)合。IP3的受體是位于內(nèi)質(zhì)網(wǎng)中的鈣通道。當(dāng)IP3與其受體結(jié)合后，鈣離子釋放到細(xì)胞質(zhì)中，從而激活各種鈣調(diào)節(jié)的細(xì)胞內(nèi)信號(hào)?；瘜W(xué)性質(zhì)播報(bào)編輯IP3的分子結(jié)構(gòu)IP3上的磷酸基根據(jù)溶液的pH存在三種不同的形式。磷原子可以通過單鍵與三個(gè)氧原子結(jié)合，并使用雙鍵/二配位鍵與第四個(gè)氧原子結(jié)合。因此，溶液的pH通過改變磷酸基的形式，決定了其與其他分子結(jié)合的能力。磷酸基與肌醇環(huán)的結(jié)合通過磷酸酯鍵合實(shí)現(xiàn)（參見磷酸和磷酸鹽）。這種鍵合涉及通過脫水反應(yīng)將肌醇環(huán)中的一個(gè)氫氧基與一個(gè)游離的磷酸基結(jié)合。考慮到平均生理pH約為7.4，生物體內(nèi)與肌醇環(huán)結(jié)合的磷酸基的主要形式是PO42-，因此IP3通常帶有凈負(fù)電荷，這對(duì)于使其與受體結(jié)合至關(guān)重要，因?yàn)樗峭ㄟ^磷酸基與受體上帶有正電荷的殘基結(jié)合。IP3在其三個(gè)氫氧基形式上有三個(gè)氫鍵供體，另外肌醇環(huán)上第6個(gè)碳原子的氫氧基也參與了IP3的結(jié)合。 [2]信號(hào)通路播報(bào)編輯細(xì)胞內(nèi)Ca2+濃度的增加通常是IP3激活的結(jié)果。當(dāng)配體結(jié)合到與G蛋白耦合的G蛋白偶聯(lián)受體（GPCR）時(shí)，Gq蛋白的α亞單位可以結(jié)合并激活PLC的同工酶PLC-β，導(dǎo)致PIP2被分解成IP3和DAG。如果受體酪氨酸激酶（RTK）參與激活該通路，同工酶PLC-γ上的酪氨酸殘基能夠在RTK激活時(shí)被磷酸化，這將激活PLC-γ并使其將PIP2分解為DAG和IP3。這發(fā)生在能夠?qū)ιL因子（如胰島素）產(chǎn)生響應(yīng)的細(xì)胞中，因?yàn)樯L因子是激活RTK的配體。由于其可溶性，IP3在PLC的作用下產(chǎn)生后，能夠通過細(xì)胞質(zhì)擴(kuò)散到內(nèi)質(zhì)網(wǎng)（ER）或肌細(xì)胞中的肌漿網(wǎng)（SR）。一旦到達(dá)ER，IP3能夠結(jié)合到三磷酸肌醇受體（Ins(1,4,5)P3R），這是一種位于ER表面的配體門控Ca2+通道。IP3作為門控通道的配體與Ins(1,4,5)P3R的結(jié)合，觸發(fā)Ca2+通道的開放，從而釋放Ca2+進(jìn)入細(xì)胞質(zhì)。在心肌細(xì)胞中，Ca2+的增加會(huì)激活SR上的Ryanodine受體控制的通道，通過一種稱為鈣致鈣釋放的過程導(dǎo)致Ca2+進(jìn)一步增加。IP3還可能通過增加細(xì)胞膜上的Ca2+濃度而間接激活細(xì)胞膜上的Ca2+通道。功能播報(bào)編輯IP3的主要功能是動(dòng)員儲(chǔ)存器官中的Ca2+并調(diào)節(jié)細(xì)胞增殖以及其他需要游離鈣的細(xì)胞反應(yīng)。例如，在平滑肌細(xì)胞中，細(xì)胞質(zhì)Ca2+濃度的增加導(dǎo)致肌細(xì)胞的收縮。 [3]在神經(jīng)系統(tǒng)中，IP3充當(dāng)?shù)诙攀?，小腦包含最高濃度的IP3受體。 [4]有證據(jù)表明IP3受體在小腦Purkinje細(xì)胞的可塑性誘導(dǎo)中發(fā)揮重要作用。相關(guān)疾病播報(bào)編輯亨廷頓病亨廷頓病發(fā)生在細(xì)胞質(zhì)蛋白亨廷頓（Htt）的N-末端區(qū)域額外添加了35個(gè)谷氨酰胺殘基時(shí)。這種修改后的Htt稱為Httexp，它使得類型1的IP3受體對(duì)IP3更為敏感，從而導(dǎo)致從內(nèi)質(zhì)網(wǎng)釋放過多的Ca2+，使細(xì)胞質(zhì)和線粒體中Ca2+濃度增加，這種增加被認(rèn)為是中型多棘神經(jīng)元降解的原因。 [5]阿爾茨海默病自1994年提出阿爾茨海默病的Ca2+假說以來，多項(xiàng)研究表明Ca2+信號(hào)紊亂是阿爾茨海默病的主要原因。家族性阿爾茨海默病與早老素1（PS1）、早老素2（PS2）和淀粉樣前體蛋白（APP）基因的突變密切相關(guān)，這些基因的突變形式都被發(fā)現(xiàn)引起內(nèi)質(zhì)網(wǎng)中Ca2+信號(hào)的異常。已經(jīng)證明PS1的突變?cè)趲追N動(dòng)物模型中增加了IP3介導(dǎo)的內(nèi)質(zhì)網(wǎng)Ca2+釋放，并使用鈣通道阻滯劑成功治療阿爾茨海默病，另外還提出使用鋰以減少IP3周轉(zhuǎn)（turnover）作為可能的治療方法。 [6]新手上路成長任務(wù)編輯入門編輯規(guī)則本人編輯我有疑問內(nèi)容質(zhì)疑在線客服官方貼吧意見反饋投訴建議舉報(bào)不良信息未通過詞條申訴投訴侵權(quán)信息封禁查詢與解封?2024?Baidu?使用百度前必讀?|?百科協(xié)議?|?隱私政策?|?百度百科合作平臺(tái)?|?京ICP證030173號(hào)?京公網(wǎng)安備110000020000【射頻芯片指標(biāo)】——三階截?cái)帱c(diǎn)IP3 - 知乎
【射頻芯片指標(biāo)】——三階截?cái)帱c(diǎn)IP3 - 知乎切換模式寫文章登錄/注冊(cè)【射頻芯片指標(biāo)】——三階截?cái)帱c(diǎn)IP3利爾達(dá)利爾達(dá)工作人員 由于放大器存在非線性效應(yīng)（BJT的e指數(shù)轉(zhuǎn)移特性和FET的二次函數(shù)轉(zhuǎn)移特性），當(dāng)輸入兩個(gè)頻率很接近的功率信號(hào)Pi（f1）和Pi（f2）時(shí)，在放大器輸出端會(huì)產(chǎn)生兩個(gè)三階交調(diào)分量Po（2f2-f1）和Po（2f1-f2）,如果f1和f2頻點(diǎn)比較接近，那么2f1-f2和2f2-f1就會(huì)比較靠近f1和f2，一般的濾波器很難濾除。由此可以想象如果f1，f2是工作信道的邊界，那么經(jīng)過放大器后在工作信道帶外將會(huì)產(chǎn)生雜散泄露?！ MD的值是衡量三階交調(diào)失真與有用信號(hào)之間差異的量，IMD=Po（f2）-Po（2f2-f1）（單位dBc），可以看出IMD越大，發(fā)射機(jī)的線性度越好?！ ≡趯?duì)數(shù)標(biāo)系中，雙音輸入輸出功率和三階交調(diào)輸出功率關(guān)系如下圖所示： Po（f2）與Pi（f2）關(guān)系曲線的斜率是1，Po（2f2-f1）與Pi（f2）的關(guān)系曲線的斜率是3，兩條曲線的交點(diǎn)定義為IP3：輸入功率就叫IIP3，輸出功率就叫OIP3; 由此讀者可以理解IP3的含義，即當(dāng)輸入功率達(dá)到IIP3時(shí)，有用信號(hào)的功率達(dá)到OIP3，三階交調(diào)的功率也是OIP3，此時(shí)IMD為0dBc，這種情況是輸出信號(hào)最惡劣的情形?！ ×硗庖峒暗氖前l(fā)射機(jī)的無失真動(dòng)態(tài)范圍df，由上圖相似三角形可輕易求出df：df（dB）=2/3[OIP3(dBm)-Po,mds(dBm)]，Po,mds定義為放大器最小輸出功率，它的值一般規(guī)定為比放大器的輸出噪聲功率大3dB，由此可以算出Po,mds（dBm）=KTB（dBm）+G（dB）+F（dB）+3dB；從曲線意義上來理解df，即當(dāng)輸入功率為某一數(shù)值P時(shí)，三階交調(diào)的功率正好淹沒于放大器的最小輸出功率里面，此時(shí)相當(dāng)于三階交調(diào)對(duì)有用信號(hào)幾乎沒有干擾，所以此時(shí)的有用信號(hào)輸出功率與放大器最小輸出功率之差定義為無失真動(dòng)態(tài)范圍?！ ∵€要談及一點(diǎn)的是級(jí)聯(lián)系統(tǒng)，雖然提高了系統(tǒng)的增益，但是整體的噪聲系數(shù)F提高了，Po,mds也提高了，級(jí)聯(lián)系統(tǒng)的OIP3降低了，所以根據(jù)上面的公式，整個(gè)系統(tǒng)的df降低了。發(fā)布于 2019-08-14 09:17射頻?贊同 37??1 條評(píng)論?分享?喜歡?收藏?申請(qǐng)
生理學(xué)中的IP3是什么？ - 知乎
生理學(xué)中的IP3是什么？ - 知乎首頁知乎知學(xué)堂發(fā)現(xiàn)等你來答?切換模式登錄/注冊(cè)生理學(xué)人體人體解剖學(xué)人體構(gòu)造人體生理學(xué)生理學(xué)中的IP3是什么？關(guān)注者2被瀏覽15,561關(guān)注問題?寫回答?邀請(qǐng)回答?好問題?添加評(píng)論?分享?1 個(gè)回答默認(rèn)排序懼色醫(yī)學(xué)狗? 關(guān)注IP3（inositol triphosphate，三磷酸肌醇），參與G蛋白耦聯(lián)受體接到的信號(hào)轉(zhuǎn)導(dǎo)的第二信使。在磷脂酰肌醇途徑中，胞外信號(hào)分子與其相應(yīng)的G蛋白偶聯(lián)受體結(jié)合后，激活膜上的Gp蛋白（一種作用于磷脂酰肌醇系統(tǒng)的G蛋白），然后由Gp蛋白激活磷酸酯酶Cβ （phospholipase Cβ，PLC）， 將膜上的4，5-二磷酸脂酰肌醇（phosphatidylinositol biphosphate， PIP2）分解為兩個(gè)細(xì)胞內(nèi)的第二信使： DAG和IP3，最后通過激活蛋白激酶C（protein kinase C，PKC），引起級(jí)聯(lián)反應(yīng)，進(jìn)行細(xì)胞的應(yīng)答。該通路也稱IP3、DAG、Ca2+信號(hào)通路。發(fā)布于 2020-04-19 14:01?贊同 4??3 條評(píng)論?分享?收藏?喜歡收起??
IP3_百度百科
IP3_百度百科
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IP3
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IP?（inositol triphosphate，三磷酸肌醇），參與G蛋白耦聯(lián)受體介導(dǎo)的信號(hào)轉(zhuǎn)導(dǎo)的第二信使。在磷脂酰肌醇途徑中，胞外信號(hào)分子與其相應(yīng)的G蛋白偶聯(lián)受體結(jié)合後，激活膜上的Gq蛋白（一種作用於磷脂酰肌醇系統(tǒng)的G蛋白），然後由Gp蛋白激活磷酸酯酶Cβ （phospholipase Cβ，PLC）， 將膜上的4，5-二磷酸脂酰肌醇（phosphatidylinositol biphosphate， PIP2）分解為兩個(gè)細(xì)胞內(nèi)的第二信使： DAG和IP?，最後通過激活蛋白激酶C（protein kinase C，PKC），引起級(jí)聯(lián)反應(yīng)，進(jìn)行細(xì)胞的應(yīng)答。該通路也稱IP?、DAG、Ca2+信號(hào)通路。
中文名
三磷酸肌醇
外文名
inositol 1,4,5-trisphosphate, IP3
水溶性
可溶
性????質(zhì)
可以從質(zhì)膜擴(kuò)散到胞質(zhì)溶膠
分子量
420.10
分子式
C6H15O15P3
目錄
1
簡介
2
化學(xué)性質(zhì)
3
信號(hào)通路
4
功能
5
相關(guān)疾病
?
亨廷頓病
?
阿爾茨海默病
IP3簡介
肌醇三磷酸（IP3）是一種肌醇磷酸信號(hào)分子。它是通過磷脂酶C（PLC）水解位於細(xì)胞膜中的磷脂酰肌醇-4,5-二磷酸（PIP2）而產(chǎn)生的。與二?；视停―AG）一樣，IP3是生物細(xì)胞信號(hào)轉(zhuǎn)導(dǎo)中使用的第二信使分子。但與DAG留在膜內(nèi)不同，IP3是可溶的，並在細(xì)胞內(nèi)擴(kuò)散，與其受體結(jié)合。IP3的受體是位於內(nèi)質(zhì)網(wǎng)中的鈣通道。當(dāng)IP3與其受體結(jié)合後，鈣離子釋放到細(xì)胞質(zhì)中，從而激活各種鈣調(diào)節(jié)的細(xì)胞內(nèi)信號(hào)。
IP3化學(xué)性質(zhì)
IP3的分子結(jié)構(gòu)
IP3上的磷酸基根據(jù)溶液的pH存在三種不同的形式。磷原子可以通過單鍵與三個(gè)氧原子結(jié)合，並使用雙鍵/二配位鍵與第四個(gè)氧原子結(jié)合。因此，溶液的pH通過改變磷酸基的形式，決定了其與其他分子結(jié)合的能力。磷酸基與肌醇環(huán)的結(jié)合通過磷酸酯鍵合實(shí)現(xiàn)（參見磷酸和磷酸鹽）。這種鍵合涉及通過脫水反應(yīng)將肌醇環(huán)中的一個(gè)氫氧基與一個(gè)遊離的磷酸基結(jié)合。考慮到平均生理pH約為7.4，生物體內(nèi)與肌醇環(huán)結(jié)合的磷酸基的主要形式是PO42-，因此IP3通常帶有淨(jìng)負(fù)電荷，這對(duì)於使其與受體結(jié)合至關(guān)重要，因?yàn)樗峭ㄟ^磷酸基與受體上帶有正電荷的殘基結(jié)合。IP3在其三個(gè)氫氧基形式上有三個(gè)氫鍵供體，另外肌醇環(huán)上第6個(gè)碳原子的氫氧基也參與了IP3的結(jié)合。
[2]?
IP3信號(hào)通路
細(xì)胞內(nèi)Ca2+濃度的增加通常是IP3激活的結(jié)果。當(dāng)配體結(jié)合到與G蛋白耦合的G蛋白偶聯(lián)受體（GPCR）時(shí)，Gq蛋白的α亞單位可以結(jié)合並激活PLC的同工酶PLC-β，導(dǎo)致PIP2被分解成IP3和DAG。如果受體酪氨酸激酶（RTK）參與激活該通路，同工酶PLC-γ上的酪氨酸殘基能夠在RTK激活時(shí)被磷酸化，這將激活PLC-γ並使其將PIP2分解為DAG和IP3。這發(fā)生在能夠?qū)ιL因子（如胰島素）產(chǎn)生響應(yīng)的細(xì)胞中，因?yàn)樯L因子是激活RTK的配體。由於其可溶性，IP3在PLC的作用下產(chǎn)生後，能夠通過細(xì)胞質(zhì)擴(kuò)散到內(nèi)質(zhì)網(wǎng)（ER）或肌細(xì)胞中的肌漿網(wǎng)（SR）。一旦到達(dá)ER，IP3能夠結(jié)合到三磷酸肌醇受體（Ins(1,4,5)P3R），這是一種位於ER表面的配體門控Ca2+通道。IP3作為門控通道的配體與Ins(1,4,5)P3R的結(jié)合，觸發(fā)Ca2+通道的開放，從而釋放Ca2+進(jìn)入細(xì)胞質(zhì)。在心肌細(xì)胞中，Ca2+的增加會(huì)激活SR上的Ryanodine受體控制的通道，通過一種稱為鈣致鈣釋放的過程導(dǎo)致Ca2+進(jìn)一步增加。IP3還可能通過增加細(xì)胞膜上的Ca2+濃度而間接激活細(xì)胞膜上的Ca2+通道。
IP3功能
IP3的主要功能是動(dòng)員儲(chǔ)存器官中的Ca2+並調(diào)節(jié)細(xì)胞增殖以及其他需要遊離鈣的細(xì)胞反應(yīng)。例如，在平滑肌細(xì)胞中，細(xì)胞質(zhì)Ca2+濃度的增加導(dǎo)致肌細(xì)胞的收縮。
[3]?
在神經(jīng)系統(tǒng)中，IP3充當(dāng)?shù)诙攀?，小腦包含最高濃度的IP3受體。
[4]?
有證據(jù)表明IP3受體在小腦Purkinje細(xì)胞的可塑性誘導(dǎo)中發(fā)揮重要作用。
IP3相關(guān)疾病
IP3亨廷頓病
亨廷頓病發(fā)生在細(xì)胞質(zhì)蛋白亨廷頓（Htt）的N-末端區(qū)域額外添加了35個(gè)谷氨醯胺殘基時(shí)。這種修改後的Htt稱為Httexp，它使得類型1的IP3受體對(duì)IP3更為敏感，從而導(dǎo)致從內(nèi)質(zhì)網(wǎng)釋放過多的Ca2+，使細(xì)胞質(zhì)和線粒體中Ca2+濃度增加，這種增加被認(rèn)為是中型多棘神經(jīng)元降解的原因。
[5]?
IP3阿爾茨海默病
自1994年提出阿爾茨海默病的Ca2+假説以來，多項(xiàng)研究表明Ca2+信號(hào)紊亂是阿爾茨海默病的主要原因。家族性阿爾茨海默病與早老素1（PS1）、早老素2（PS2）和澱粉樣前體蛋白（APP）基因的突變密切相關(guān)，這些基因的突變形式都被發(fā)現(xiàn)引起內(nèi)質(zhì)網(wǎng)中Ca2+信號(hào)的異常。已經(jīng)證明PS1的突變?cè)趲追N動(dòng)物模型中增加了IP3介導(dǎo)的內(nèi)質(zhì)網(wǎng)Ca2+釋放，並使用鈣通道阻滯劑成功治療阿爾茨海默病，另外還提出使用鋰以減少IP3週轉(zhuǎn)（turnover）作為可能的治療方法。
[6]?
參考資料
1.
??
Inositol trisphosphate and calcium signalling mechanisms?
．ScienceDirect[引用日期2023-12-12]
2.
??
Structural insights into the regulatory mechanism of IP3 receptor?
．ScienceDirect[引用日期2023-12-12]
3.
??
Signal transduction and regulation in smooth muscle?
．Nature[引用日期2023-12-12]
4.
??
Inositol 1,4,5-trisphosphate receptor binding: autoradiographic localization in rat brain?
．PubMed[引用日期2023-12-12]
5.
??
Deranged neuronal calcium signaling and Huntington disease?
．ScienceDirect[引用日期2023-12-12]
6.
??
Michael J. Berridge．The Inositol Trisphosphate/Calcium Signaling Pathway in Health and Disease：American Physiological Society，2016
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失真1--線性度概念(1dB壓縮點(diǎn),IP3,OP3) - 知乎
失真1--線性度概念(1dB壓縮點(diǎn),IP3,OP3) - 知乎首發(fā)于Analog/RF IC Design切換模式寫文章登錄/注冊(cè)失真1--線性度概念(1dB壓縮點(diǎn),IP3,OP3)Shuiniu死磕RFIC線性度的相關(guān)基本概念在很多教材上都已經(jīng)說明，最近再次溫故，收益匪淺，同時(shí)對(duì)失真進(jìn)行深入的研究和學(xué)習(xí)，分享下心得。本文主要介紹下線性度的基本概念，包括1dB壓縮點(diǎn),IP3,OP3，注重公式的推導(dǎo)。電路存在非線性是個(gè)普遍現(xiàn)象，通常用1dB壓縮點(diǎn)和三階交調(diào)點(diǎn)來描述電路的非線性?？梢杂锰├占?jí)數(shù)展開來表達(dá)電路的輸入輸出特性：其中a1作為電路的小信號(hào)增益,a2和a3是高階非線性系數(shù)，當(dāng)輸入一個(gè)正弦信號(hào)x(t)=Acos(wt) ，帶入上式，忽略三次以上的非線性，得到：其中第一項(xiàng)是直流分量，直流分量是由偶次諧波產(chǎn)生的，如果是全差分電路，那么偶次諧波將被消除，直流分量也就消除了，但是當(dāng)電路存在失配時(shí)仍會(huì)導(dǎo)致有限的偶次諧波。第二項(xiàng)為基波分量，是想要的分量；后二項(xiàng)分別是二次諧波和三次諧波，諧波分量的幅值和輸入信號(hào)幅值A(chǔ)的關(guān)系分別是平方關(guān)系和三次方關(guān)系。當(dāng)電路存在選頻網(wǎng)絡(luò)時(shí)，高次諧波分量被濾除，通過隔直電容或者全差分電路時(shí)消除直流分量后，只剩下基波分量，如果不存在著非線性，即a2=a3=0, 那么理想的線性系統(tǒng)的輸出為：而非線性導(dǎo)致輸出為:增益為 : 輸入輸出響應(yīng)偏離線性關(guān)系，對(duì)于射頻電路，通常a1*a3<1，因此增益受到壓縮，當(dāng)增益偏離線性增益1dB時(shí)，對(duì)應(yīng)的輸入信號(hào)幅值為輸入1dB壓縮點(diǎn) A_{in,1dB} ，對(duì)應(yīng)的輸出信號(hào)幅值為輸出1dB壓縮點(diǎn)A_{out,1dB} ，輸入輸出幅值也可以用功率值替代，表示為 IP_{1dB} 和OP_{1dB} 。如圖所示表示1dB壓縮點(diǎn)，計(jì)算輸入1dB壓縮點(diǎn)，即增益降低1dB的輸入幅度值：除了用1dB壓縮點(diǎn)描述非線性外，另一種描述非線性的方法是互調(diào)失真，當(dāng)輸入二個(gè)頻率的信號(hào)，不同頻率分量會(huì)產(chǎn)生互調(diào)分量 2w1-w2 和 2w2-w1 ，這些分量可能會(huì)對(duì)輸出信號(hào)產(chǎn)生干擾，令 x(t)=A1cos(w1t)+A2cos(w2t) ，忽略三次以上的非線性，帶入上面公式得：經(jīng)化簡產(chǎn)生的基波頻率分量為：二階交調(diào) \omega_{1}\pm\omega_{2} 分量為：三階交調(diào) 2\omega_{1}\pm\omega_{2} 分量為：三階交調(diào) 2\omega_{2}\pm\omega_{1} 分量為：令二個(gè)輸入頻率的幅度相同，即 A1=A2=A ，且假設(shè)A是個(gè)比較小的值，可簡化基波分量為 a_{1}A(cos\omega_{1}t+cos\omega_{2}t) ，把二階交調(diào)歸一化到基波分量上，得到 ： 把三階交調(diào)歸一化到基波分量（三階交調(diào)的高頻分量不考慮），得到 ：在差分系統(tǒng)中，二階非線性被抵消了，因此，更加關(guān)注三階交調(diào)點(diǎn)，當(dāng)基波幅度和三階交調(diào)幅度相等時(shí)，即令 IM_{3 } =1 ，得到輸出三階交調(diào)點(diǎn) ： 對(duì)應(yīng)的輸出表示為輸出三階交調(diào) A_{OIP3} ，如圖s所示表示三階交調(diào)點(diǎn)，比較輸入1dB壓縮點(diǎn)和輸入三階交調(diào)點(diǎn)，得到：利用MOS晶體管構(gòu)成的差分對(duì)時(shí)，忽略電路失調(diào)失配的影響，有下面結(jié)論：提高差分對(duì)MOS管的過驅(qū)動(dòng)電壓有利于提高線性度。當(dāng)多個(gè)子系統(tǒng)級(jí)聯(lián)時(shí)，可以推導(dǎo)出以下結(jié)論：其中 A_{IP3} 表示整體系統(tǒng)的輸入三階交調(diào)點(diǎn)， a_{n} 表示第n級(jí)子系統(tǒng)的增益， A_{IP3,n} 表示第n級(jí)子系統(tǒng)的三階交調(diào)點(diǎn)。如果級(jí)聯(lián)的每一級(jí)的增益都大于1，那么后級(jí)對(duì)整體系統(tǒng)的影響更大，直觀的理解是信號(hào)每經(jīng)過一級(jí)，都被放大，因此產(chǎn)生的非線性更加嚴(yán)重。好了，總結(jié)完畢，后期再會(huì)。發(fā)布于 2020-06-10 22:53非線性諧波失真模擬電路?贊同 51??8 條評(píng)論?分享?喜歡?收藏?申請(qǐng)轉(zhuǎn)載?文章被以下專欄收錄Analog/RF IC Des
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【譯】三階截點(diǎn)（IP3）的物理意義
2021-11-12
SDR, 中文, 翻譯
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Word Count: 833(words)
Read Count: 2(minutes)
原文鏈接：What is physical significance of IP3, why it is more important in Receiver Chain ?
了解三階截點(diǎn)（IP3）的物理意義
當(dāng)一個(gè)放大器或其他電路變得非線性時(shí)，它將開始產(chǎn)生放大的輸入的諧波。二次、三次和更高次的諧波通常在放大器帶寬之外，所以它們通常很容易過濾掉。然而，非線性也會(huì)產(chǎn)生兩個(gè)或多個(gè)信號(hào)的混合效應(yīng)。
如果信號(hào)的頻率很接近，產(chǎn)生的一些稱為互調(diào)產(chǎn)物（Intermodulation products）的和差頻率會(huì)出現(xiàn)在放大器的預(yù)期工作帶寬內(nèi)。這些不能被過濾掉，所以它們最終會(huì)成為被放大的主要信號(hào)中的干擾信號(hào)。
舉例來說：接收鏈中的期望輸入信號(hào)（F0）在 1750MHz，兩個(gè)不期望的信號(hào)，F(xiàn)1=1760，F(xiàn)2=1770，所以當(dāng)兩個(gè)不期望的信號(hào)混合時(shí)，它們會(huì)產(chǎn)生三階互調(diào)產(chǎn)物，其中一個(gè)在（2*F1-F2）落在 1750MHz，這也是期望信號(hào)的頻率，因此期望信號(hào)的 SNR 會(huì)降低。
三階互調(diào)產(chǎn)物的功率水平取決于設(shè)備或放大器的線性度，以三階截點(diǎn)（IP3）表示。
三階截點(diǎn)（IP3）處的輸出越高，線性度越好，互調(diào)擾動(dòng)（IMD）越低。IP3 值本質(zhì)上表明在 IMD 發(fā)生之前，放大器可以處理多大的信號(hào)。例如，IP3 值為 25 dBm 比 18 dBm 的要好。
為什么 IP3 在接收鏈中被測(cè)量
在接收鏈中，多個(gè)信號(hào)通過天線端口輸入，由于干擾信號(hào)在天線端口的混合，產(chǎn)生的 IMD 會(huì)在所需的頻段混合，從而影響所需信號(hào)的信噪比。我們無法控制天線端口的干擾信號(hào)，因?yàn)樵诳諝庵写嬖谥煌l率的不同類型的信號(hào)。它們中的少數(shù)會(huì)在所需的頻段上引起 IMD。
因此，測(cè)量接收器的三階輸入截點(diǎn)（IIP3）變得非常重要，以確保它產(chǎn)生多少影響信噪比的 IMD 水平。
接收器鏈的 IIP3 值越高，性能就越好，因?yàn)?IMD 功率水平更低。因此，它表明一個(gè)設(shè)備（如放大器）或系統(tǒng)（如接收器）在強(qiáng)信號(hào)下的表現(xiàn)如何。
發(fā)射器鏈中的 IP3 是什么？
在發(fā)射鏈中，通常 IP3 規(guī)格不太重要，因?yàn)樵诎l(fā)射鏈中產(chǎn)生的信號(hào)通常是單載波，不會(huì)產(chǎn)生 IMD。例如，在單載波 GSM 中，傳輸?shù)氖且粋€(gè)載波信號(hào)，不會(huì)產(chǎn)生 IMD。在多載波 GSM 中，會(huì)產(chǎn)生 IMD，因?yàn)榘l(fā)射鏈中的多個(gè)信號(hào)混合在一起，產(chǎn)生互調(diào)產(chǎn)物。在多載波系統(tǒng)中，發(fā)射器鏈中的輸出截點(diǎn)被測(cè)量（OIP3）或發(fā)揮著重要作用。
在 LTE 系統(tǒng)中，只產(chǎn)生一個(gè)載波，所以 OIP3 就不那么重要了。在 LTE Advanced 中，由于載波聚合，會(huì)產(chǎn)生多個(gè)載波，所以 OIP3 在這種情況下很重要。
但是，即使在發(fā)射機(jī)鏈中產(chǎn)生了單載波，在任何情況下，干擾信號(hào)都可能通過天線端口以相反的方向進(jìn)入發(fā)射機(jī)鏈而導(dǎo)致互調(diào)產(chǎn)物，所以通常在發(fā)射機(jī)鏈中測(cè)量反向互調(diào)。
Permanent Link：
https://blog.inoki.cc/2021/11/12/Physical-significance-iip3-important-receiver-chain/
InokiComputer Scientist
Ph.D in Computer Science, major in Embedded System and AI.
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三階互調(diào)的計(jì)算及IP3測(cè)試原理和方法 - 21ic電子網(wǎng)
三階互調(diào)的計(jì)算及IP3測(cè)試原理和方法 - 21ic電子網(wǎng)
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三階互調(diào)的計(jì)算及IP3測(cè)試原理和方法
時(shí)間：2017-12-14 14:24:12
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ip3 ??
三階互調(diào) ??
測(cè)試原理 ??
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[導(dǎo)讀]三階交截點(diǎn)(IP3)是衡量通信系統(tǒng)線性度的一個(gè)重要指標(biāo)，他反映了系統(tǒng)受到強(qiáng)信號(hào)干擾時(shí)互調(diào)失真的大小。當(dāng)系統(tǒng)的IP3較高時(shí)，要精確測(cè)試IP3會(huì)比較困難，因?yàn)闇y(cè)試環(huán)境中各種因素(如測(cè)試配件的隔離度、線性度和匹配性等)都容易影響高IP3的測(cè)試。
三階交截點(diǎn)(IP3)是衡量通信系統(tǒng)線性度的一個(gè)重要指標(biāo)，他反映了系統(tǒng)受到強(qiáng)信號(hào)干擾時(shí)互調(diào)失真的大小。當(dāng)系統(tǒng)的IP3較高時(shí)，要精確測(cè)試IP3會(huì)比較困難，因?yàn)闇y(cè)試環(huán)境中各種因素(如測(cè)試配件的隔離度、線性度和匹配性等)都容易影響高IP3的測(cè)試。下面將簡略介紹IP3的測(cè)試原理，詳細(xì)分析高IP3的測(cè)試方法。
1 IP3測(cè)試原理
在無線通信設(shè)備中，器件(如放大器、混頻器、調(diào)制/解調(diào)器等)的非線性通常會(huì)使同時(shí)侵入2個(gè)或多個(gè)強(qiáng)干擾信號(hào)發(fā)生相互調(diào)制，并產(chǎn)生新的頻率成分，這種現(xiàn)象稱為互調(diào)。互調(diào)干擾不僅能降低有用信號(hào)的功率，引起信號(hào)失真，降低系統(tǒng)選擇性，還能破壞鄰近信道的性能。因此，互調(diào)性能是系統(tǒng)常檢指標(biāo)，通常用IP3來表示。
IP3是工作頻率信號(hào)在理想線性系統(tǒng)中的輸出信號(hào)與三階互調(diào)分量幅值相等時(shí)的交點(diǎn)，是一個(gè)固定點(diǎn)。如圖1所示[1]。該點(diǎn)是虛交點(diǎn)，實(shí)際系統(tǒng)中無法直接測(cè)出，但可以通過相關(guān)的測(cè)量值計(jì)算出來。下面將簡單介紹IP3計(jì)算式的原理。
雖然侵入系統(tǒng)的強(qiáng)信號(hào)可能有2個(gè)或2個(gè)以上，但為了測(cè)試的方便，假設(shè)只有2個(gè)強(qiáng)的等幅單音信號(hào)侵入了系統(tǒng)。若用一個(gè)冪級(jí)數(shù)來表示器件的非線性作用，并假設(shè)單音信號(hào)的頻率分別為f1和f2，那么不難推出三階互調(diào)分量的頻率為(2f1-f2)或(2f2-f1)。IP3(IIP3，OIP3)的計(jì)算式為[2]：
其中：IIP3為輸入IP3，是IP3的橫坐標(biāo);
OIP3為輸出IP3，是IP3的縱坐標(biāo);
Pin為單音信號(hào)的輸入功率電平;
Pout為單音信號(hào)的輸出功率電平;
G為被測(cè)件(Device Under Test - DUT)的小信號(hào)增益。
IMD3為三階互調(diào)失真，他等于干擾信號(hào)的輸出功率電平減去三階互調(diào)量功率電平的值，即：
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式(2)中各元素的關(guān)系如圖2所示。由式(1)和(2)可知，如果測(cè)出單音信號(hào)的輸入/輸出功率和三階互調(diào)分量的電平值，就可求出輸入/輸出IIP3的值。
2 高IP3的測(cè)試方法
IP3的一般測(cè)試方法是按照?qǐng)D3搭建測(cè)試環(huán)境，向DUT輸入2個(gè)強(qiáng)的單音信號(hào)，測(cè)出DUT輸出端單音信號(hào)的電平和三階互調(diào)產(chǎn)物的電平，再利用式(1)和式(2)計(jì)算出IP3的大小。
當(dāng)DUT的線性度較好時(shí)，其IP3較高。測(cè)試這種IP3有2個(gè)特點(diǎn)：一是輸入的單音信號(hào)很強(qiáng);二是產(chǎn)生的三階互調(diào)分量很弱。由于強(qiáng)信號(hào)輸入容易使測(cè)試系統(tǒng)其他器件也進(jìn)入非線性狀態(tài)，產(chǎn)生同頻的互調(diào)分量或其他雜波;弱互調(diào)分量容易被大信號(hào)掩蓋，所以高IP3的測(cè)試工作不能簡單按照一般測(cè)試方法進(jìn)行，需做一些改進(jìn)：
(1)選用高質(zhì)量的信號(hào)源
信號(hào)源本身具有非線性，有一定的動(dòng)態(tài)范圍。當(dāng)信號(hào)源輸出大功率信號(hào)時(shí)，一些器件進(jìn)入非線性狀態(tài)，使得輸出信號(hào)質(zhì)量大大降低，如含有各種雜波或多次諧波。因此需選用高質(zhì)量的信號(hào)源，如合成信號(hào)源，他的線性度較高，噪聲比較低。
(2)隔離2個(gè)信號(hào)源，減小他們的相互作用 如果不隔離2個(gè)信號(hào)源，他們的自適應(yīng)邏輯電路會(huì)相互作用產(chǎn)生互調(diào)分量[3]，影響DUT弱互調(diào)分量的測(cè)試。因此最好在每個(gè)信號(hào)源與功率合成器之間加一個(gè)隔離器。鐵氧體磁性材料隔離器是較理想的選擇，因?yàn)樗母綦x度高，差損小。也可以選用10～20 dB的固定衰減器來隔離，但他們的隔離度不高，為了補(bǔ)償衰減器的衰減量需要加大信號(hào)源的輸出功率，因此采用固定衰減器不是理想選擇。
(3)選用線性好的功率合成器
功率合成器也有一定的非線性，遭遇強(qiáng)信號(hào)時(shí)也會(huì)產(chǎn)生同頻互調(diào)分量，如果他的互調(diào)分量較大，就會(huì)掩蓋DUT產(chǎn)生的弱互調(diào)分量。因此，需采用易匹配且線性度高的功率合成器，如阻性功率合成器。他基本上完全線性，自己不會(huì)產(chǎn)生互調(diào)分量，并且各個(gè)端口具有良好的匹配性。
(4)增強(qiáng)測(cè)試系統(tǒng)的匹配性
系統(tǒng)的匹配性非常重要，為確保系統(tǒng)的良好匹配，可在功率合成器與DUT之間和頻譜儀與DUT之間分別加一個(gè)6～10 dB的固定衰減器[3]。系統(tǒng)統(tǒng)一采用50Ω匹配。
(5)選用動(dòng)態(tài)范圍大的頻譜分析儀
頻譜儀的動(dòng)態(tài)范圍是指在能以給定不確定度測(cè)量較小信號(hào)的頻譜分析儀輸入端同時(shí)存在的最大信號(hào)與最小信號(hào)之比。當(dāng)測(cè)試高IP3時(shí)，輸入頻譜儀的單音信號(hào)幅度很大而三階互調(diào)分量幅度又很小，如果頻譜儀的動(dòng)態(tài)范圍不夠?qū)o法同時(shí)測(cè)出這2種信號(hào)的大小，因此需選用大動(dòng)態(tài)范圍的頻譜分析儀。
(6)需判別測(cè)試結(jié)果的有效性
頻譜分析儀的前端結(jié)構(gòu)如圖4所示。頻譜分析儀的IP3通常不高，如安捷倫PSA系列頻譜儀(E444xA)在混頻器輸入電平為-30 dBm時(shí)，其IIP3小于+20 dBm。所以測(cè)試高IP3時(shí)不能忽略頻譜儀的非線性，輸入DUT的強(qiáng)單音信號(hào)也會(huì)在頻譜儀中相互調(diào)制產(chǎn)生同頻的互調(diào)分量。當(dāng)該互調(diào)分量較大時(shí)就需判斷頻譜儀上顯示的互調(diào)分量主要是DUT產(chǎn)生的還是頻譜儀自身產(chǎn)生的，即判斷測(cè)試結(jié)果是否有效。下面總結(jié)了3種判斷方法：
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①改變頻譜儀射頻輸入衰減器的衰減量(如加大或減小10 dB)，觀察互調(diào)分量的電平值是否相應(yīng)減少或增加。如果該電平值改變了，則說明頻譜儀產(chǎn)生的互調(diào)分量電平值不能忽略，測(cè)試結(jié)果無效。這是最簡單的判斷方法。
②在其他條件不變的情況下，比較加上DUT和不加DUT測(cè)得的互調(diào)分量電平值。如果后者的電平值比前者的小得多則說明所測(cè)結(jié)果是DUT產(chǎn)生的互調(diào)分量;否則，測(cè)試結(jié)果無效。
③一般的頻譜儀手則上都會(huì)給出在混頻器輸入信號(hào)電平為某個(gè)值(如-30 dBm)時(shí)各個(gè)頻段三階互調(diào)失真的大小或直接給出各個(gè)頻段IIP3的值。因此，可利用式(1)和式(2)計(jì)算頻譜分析儀產(chǎn)生的三階互調(diào)分量大小。比較計(jì)算結(jié)果與測(cè)試結(jié)果，如果計(jì)算值比測(cè)試結(jié)果小得多，則測(cè)試結(jié)果為有效值。
當(dāng)測(cè)試結(jié)果無效時(shí)，解決辦法之一是減小2個(gè)單音信號(hào)的輸入電平或加大頻譜儀輸入衰減器的衰減量。另一種是用測(cè)試結(jié)果(dBm轉(zhuǎn)化為mW)減去利用判斷方法③得出的頻譜儀互調(diào)分量大小(mW)，從而得到DUT互調(diào)分量的大小(mW)。
在測(cè)試過程中還需注意：
(1)IP3的計(jì)算式(1)是在假設(shè)輸入DUT的2個(gè)干擾信號(hào)電平相等的前提下得到的。如果2個(gè)干擾信號(hào)電平不等，計(jì)算公式需調(diào)整[1]：
(2)一般情況下，當(dāng)2個(gè)單音信號(hào)的幅度均減少1 dB時(shí)，三階互調(diào)分量的電平值會(huì)減少3 dB，IMD3將相應(yīng)增加2dB。可見，減少單音信號(hào)的輸入幅度可大大減少三階互調(diào)分量的幅度。
因此，要減少測(cè)試環(huán)境中其他配件的非線性對(duì)測(cè)試結(jié)果的影響，最行之有效的方法是盡可能地減小單音信號(hào)的電平值。
(3)測(cè)試環(huán)境中的連接電纜應(yīng)盡量不要彎曲(特別是在接頭處)，以防止增加信號(hào)反射，產(chǎn)生過多的互調(diào)產(chǎn)物，影響測(cè)試準(zhǔn)確性。為保持測(cè)試系統(tǒng)互調(diào)特性的穩(wěn)定，測(cè)試環(huán)境不要輕易挪動(dòng)，每個(gè)端口的接頭都要擰緊。
3 實(shí) ? ?驗(yàn)
根據(jù)該測(cè)試方法，對(duì)CDMA2000基站接收通道射頻輸入部分(從低噪聲放大器輸出端到第一混頻器輸出端)的IP3進(jìn)行了測(cè)試。其測(cè)試原理圖如圖5所示。其中，E4432B和E4440A均為Agilent公司的測(cè)試儀器。信號(hào)源輸出的單音信號(hào)頻率是根據(jù)3GPP2協(xié)議要求來確定的：分別偏離中心頻率(454 MHz)+900 kHz和+1700 kHz。
在混頻器輸出端的信號(hào)頻率分別為70.9 MHz和71.7 MHz，即分別偏離中頻頻率(70 MHz)+900 kHz和+1 700 kHz，用E4440A測(cè)得DUT信號(hào)經(jīng)衰減器后的電平值均為-17.8 dBm。表1是測(cè)試結(jié)果。
如果采用一般的測(cè)試方法，得到的IIP3值為28.7 dBm。由此可見，采用上面介紹的高IP3測(cè)試方法，大大提高了高IP3的測(cè)試準(zhǔn)確度。
4 結(jié) 語
隨著無線通信的快速發(fā)展，通信產(chǎn)品需達(dá)到的指標(biāo)要求越來越高，精確測(cè)量產(chǎn)品性能愈為重要。線性度是影響系統(tǒng)性能提高的重要因素，做好IP3的準(zhǔn)確測(cè)試工作是研究并提高系統(tǒng)線性度的一個(gè)重要前提。本高IP3測(cè)試方法已在3G基站射頻部分的IP3測(cè)試中得到較好應(yīng)用，希望能對(duì)其他產(chǎn)品的IP3測(cè)試工作有所幫助。
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作者：zhanghao
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使用萬用表測(cè)試電機(jī)好壞的原理主要基于電機(jī)的工作原理和電氣特性。電機(jī)通常是由繞組(線圈)和磁鐵構(gòu)成的，當(dāng)繞組通電時(shí)，會(huì)產(chǎn)生磁場，與磁鐵相互作用，從而使電機(jī)轉(zhuǎn)動(dòng)。因此，電機(jī)的正常工作與繞組的電氣性能密切相關(guān)。
關(guān)鍵字：
萬用表
[測(cè)試測(cè)量]
萬用表測(cè)電阻
數(shù)字萬用表是目前最常見和廣泛使用的類型。它使用數(shù)字顯示屏來顯示測(cè)量結(jié)果，具有高精度、易讀性和多功能的特點(diǎn)。數(shù)字萬用表通常具有自動(dòng)量程選擇、數(shù)據(jù)保持、相對(duì)測(cè)量、峰值保持等功能。它們還可以進(jìn)行溫度測(cè)量、電容測(cè)量和連續(xù)性測(cè)試等...
關(guān)鍵字：
萬用表
電阻測(cè)量
[測(cè)試測(cè)量]
萬用表怎么測(cè)電壓
數(shù)字萬用表內(nèi)部包含了轉(zhuǎn)換電路、模/數(shù)(A/D)轉(zhuǎn)換器、電子計(jì)數(shù)器、邏輯控制電路和譯碼顯示電路等部分，這些部分協(xié)同工作以實(shí)現(xiàn)電壓、電流和電阻的測(cè)量。
關(guān)鍵字：
萬用表
電壓測(cè)量
[測(cè)試測(cè)量]
萬用表使用入門
萬用表又稱為復(fù)用表、多用表、三用表、繁用表等，是電力電子等部門不可缺少的測(cè)量儀表，一般以測(cè)量電壓、電流和電阻為主要目的。萬用表按顯示方式分為指針萬用表和數(shù)字萬用表。
關(guān)鍵字：
萬用表
電流測(cè)量
[測(cè)試測(cè)量]
激光雷達(dá)傳感器的分類
以下內(nèi)容中，小編將對(duì)激光雷達(dá)傳感器的相關(guān)內(nèi)容進(jìn)行著重介紹和闡述，希望本文能幫您增進(jìn)對(duì)激光雷達(dá)傳感器的了解，和小編一起來看看吧。
關(guān)鍵字：
傳感器
激光雷達(dá)
激光雷達(dá)傳感器
[測(cè)試測(cè)量]
萬用表的測(cè)量使用方法
萬用表又稱為復(fù)用表、多用表、三用表、繁用表等，是電力電子等部門不可缺少的測(cè)量儀表，一般以測(cè)量電壓、電流和電阻為主要目的。
關(guān)鍵字：
萬用表
電阻測(cè)量
[測(cè)試測(cè)量]
短路分析的目的
短路分析的目的是什么呢，一般是確保電氣系統(tǒng)安全與可靠性。隨著科技的不斷進(jìn)步和電氣系統(tǒng)的廣泛應(yīng)用，短路分析在電氣工程中扮演著至關(guān)重要的角色。短路是指電氣系統(tǒng)中兩個(gè)或多個(gè)不期望的導(dǎo)體部分之間形成低阻抗通路的情況，可能導(dǎo)致電流...
關(guān)鍵字：
短路分析
電氣系統(tǒng)
[測(cè)試測(cè)量]
激光雷達(dá)毫米波雷的區(qū)別
傳感器技術(shù)在現(xiàn)代科技領(lǐng)域扮演著越來越重要的角色。其中，激光雷達(dá)和毫米波雷達(dá)作為兩種關(guān)鍵的傳感器技術(shù)，各自具有獨(dú)特的優(yōu)勢(shì)和應(yīng)用場景。本文將深入探討激光雷達(dá)與毫米波雷達(dá)之間的區(qū)別，并分析它們?cè)诳萍碱I(lǐng)域中的應(yīng)用。
關(guān)鍵字：
激光雷達(dá)
毫米波雷
傳感器
[測(cè)試測(cè)量]
蘋果激光雷達(dá)有什么作用
蘋果公司一直以來都在科技領(lǐng)域引領(lǐng)著創(chuàng)新的風(fēng)潮。其眾多產(chǎn)品中，激光雷達(dá)技術(shù)是一個(gè)不可忽視的重要元素。激光雷達(dá)，也稱為LiDAR(Light Detection and Ranging)，是一種通過測(cè)量激光脈沖與目標(biāo)物體之間...
關(guān)鍵字：
蘋果
激光雷達(dá)
[測(cè)試測(cè)量]
激光雷達(dá)的應(yīng)用
隨著科技的飛速發(fā)展，激光雷達(dá)技術(shù)以其高精度、高效率和高可靠性的特點(diǎn)，在眾多領(lǐng)域找到了廣泛的應(yīng)用。激光雷達(dá)，一種主動(dòng)式傳感器，通過向目標(biāo)發(fā)射激光脈沖并測(cè)量其反射回來的時(shí)間，可以精確地計(jì)算出目標(biāo)物體的距離、速度和其他關(guān)鍵參數(shù)...
關(guān)鍵字：
激光雷達(dá)
雷達(dá)
傳感器
[測(cè)試測(cè)量]
激光雷達(dá)與攝像頭的區(qū)別
激光雷達(dá)與攝像頭：原理、應(yīng)用與未來發(fā)展怎么樣呢?隨著自動(dòng)駕駛、機(jī)器人導(dǎo)航、無人機(jī)飛行等技術(shù)的快速發(fā)展，感知和識(shí)別周圍環(huán)境成為了這些技術(shù)的核心需求。在這個(gè)過程中，激光雷達(dá)和攝像頭成為了兩種不可或缺的傳感器。雖然它們都是感知...
關(guān)鍵字：
激光雷達(dá)
攝像頭
[測(cè)試測(cè)量]
激光雷達(dá)的掃描角度
今天說說激光雷達(dá)的掃描角度，它的技術(shù)原理、應(yīng)用與挑戰(zhàn)是什么呢?激光雷達(dá)，作為一種主動(dòng)式遙感設(shè)備，通過發(fā)射激光并接收其反射信號(hào)來獲取目標(biāo)物體的距離、速度和其他相關(guān)信息。掃描角度作為激光雷達(dá)的關(guān)鍵參數(shù)，決定了其探測(cè)范圍和分辨...
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激光雷達(dá)
掃描
[測(cè)試測(cè)量]
激光雷達(dá)測(cè)速原理
隨著科技的飛速發(fā)展，激光雷達(dá)測(cè)速技術(shù)憑借其高精度、遠(yuǎn)距離和非接觸性測(cè)量等特點(diǎn)，在眾多領(lǐng)域得到了廣泛應(yīng)用。本文詳細(xì)闡述了激光雷達(dá)測(cè)速的原理，分析了其關(guān)鍵技術(shù)，并探討了激光雷達(dá)在現(xiàn)代科技中的應(yīng)用和發(fā)展趨勢(shì)。
關(guān)鍵字：
激光雷達(dá)
測(cè)速原理
多普勒效應(yīng)
[測(cè)試測(cè)量]
激光雷達(dá)攝像頭有什么作用
激光雷達(dá)攝像頭，也稱為激光雷達(dá)傳感器或激光掃描攝像頭，是一種集成了激光雷達(dá)技術(shù)和攝像頭技術(shù)的先進(jìn)傳感器。它結(jié)合了激光雷達(dá)的高精度測(cè)距能力和攝像頭的圖像獲取功能，從而能夠同時(shí)提供目標(biāo)物體的距離信息和視覺信息。
關(guān)鍵字：
激光雷達(dá)
攝像頭
[測(cè)試測(cè)量]
激光雷達(dá)工作原理是什么
隨著科技的飛速發(fā)展，激光雷達(dá)作為一種先進(jìn)的探測(cè)技術(shù)，已廣泛應(yīng)用于自動(dòng)駕駛、航空測(cè)繪、機(jī)器人導(dǎo)航、氣象觀測(cè)等多個(gè)領(lǐng)域。激光雷達(dá)憑借其高精度、高效率和高可靠性的特點(diǎn)，為我們的生活帶來了革命性的改變。本文將詳細(xì)解析激光雷達(dá)的工...
關(guān)鍵字：
激光雷達(dá)
傳感器
[測(cè)試測(cè)量]
激光雷達(dá)傳感器原理
隨著科技的飛速發(fā)展，傳感器技術(shù)已成為眾多領(lǐng)域中的核心技術(shù)之一。在眾多傳感器中，激光雷達(dá)傳感器因其高精度、高效率和高可靠性而備受關(guān)注。本文將對(duì)激光雷達(dá)傳感器的原理進(jìn)行深入探討，并詳細(xì)闡述其在現(xiàn)代科技中的應(yīng)用，以期為讀者提供...
關(guān)鍵字：
激光雷達(dá)
傳感器
[測(cè)試測(cè)量]
激光雷達(dá)測(cè)量工作原理
在科技日新月異的今天，激光雷達(dá)測(cè)量技術(shù)以其高精度、高效率和高可靠性，在眾多領(lǐng)域發(fā)揮著至關(guān)重要的作用。從無人駕駛汽車到航空測(cè)繪，從機(jī)器人導(dǎo)航到氣象觀測(cè)，激光雷達(dá)測(cè)量技術(shù)已經(jīng)成為現(xiàn)代社會(huì)不可或缺的組成部分。本文將對(duì)激光雷達(dá)測(cè)...
關(guān)鍵字：
激光雷達(dá)
雷達(dá)
無人駕駛
測(cè)試測(cè)量
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Reference #18.26100217.1709810482.1775631b
Structural basis for activation and gating of IP3 receptors | Nature Communications
Structural basis for activation and gating of IP3 receptors | Nature Communications
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Structural basis for activation and gating of IP3 receptors
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Published: 17 March 2022
Structural basis for activation and gating of IP3 receptors
Emily A. Schmitz?
ORCID: orcid.org/0000-0002-5122-89911,2?na1, Hirohide Takahashi?
ORCID: orcid.org/0000-0002-2553-88061,2?na1 & Erkan Karakas?
ORCID: orcid.org/0000-0001-6552-31851,2?
Nature Communications
volume?13, Article?number:?1408 (2022)
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Calcium channelsCryoelectron microscopyMembrane proteinsMolecular conformationPermeation and transport
AbstractA pivotal component of the calcium (Ca2+) signaling toolbox in cells is the inositol 1,4,5-triphosphate (IP3) receptor (IP3R), which mediates Ca2+ release from the endoplasmic reticulum (ER), controlling cytoplasmic and organellar Ca2+ concentrations. IP3Rs are co-activated by IP3 and Ca2+, inhibited by Ca2+ at high concentrations, and potentiated by ATP. However, the underlying molecular mechanisms are unclear. Here we report cryo-electron microscopy (cryo-EM) structures of human type-3 IP3R obtained from a single dataset in multiple gating conformations: IP3-ATP bound pre-active states with closed channels, IP3-ATP-Ca2+ bound active state with an open channel, and IP3-ATP-Ca2+ bound inactive state with a closed channel. The structures demonstrate how IP3-induced conformational changes prime the receptor for activation by Ca2+, how Ca2+ binding leads to channel opening, and how ATP modulates the activity, providing insights into the long-sought questions regarding the molecular mechanism underpinning receptor activation and gating.
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IntroductionIP3Rs are intracellular Ca2+ channels, predominantly localized to the ER and activated by the binding of IP3 generated in response to external stimulation of G-protein coupled receptors1,2,3. Opening of the IP3Rs results in the rapid release of Ca2+ from the ER lumen into the cytoplasm, triggering diverse signaling cascades that regulate physiological processes such as learning, fertilization, gene expression, and apoptosis. Dysfunctional IP3Rs cause abnormal Ca2+ signaling and are associated with many diseases, including diabetes, cancer, and neurological disorders4,5. There are three IP3R subtypes (IP3R-1, -2, and -3) that share 60–70% sequence identity, form homo- or hetero-tetramers, exhibit different spatial expression profiles, and are involved in different signaling pathways1,2,3. Each IP3R subunit is about 2700 amino acids in length and contains a transmembrane domain (TMD) and a large cytoplasmic region comprising two β-trefold domains (βTF1 and βTF2), three Armadillo repeat domains (ARM1, ARM2, and ARM3), a central linker domain (CLD), a juxtamembrane domain (JD), and a short C-terminal domain (CTD)6,7,8,9,10 (Fig.?1).Fig. 1: Cryo-EM structures of hIP3R-3 in multiple conformations.a Domain boundaries of hIP3R-3. b–d Composite maps of hIP3R-3 in pre-active A (b), active (c), inactive (d) conformations. Each domain in one of the subunits is colored as in (a). Maps within the boxes, shown transparent, are close-up views of the Ca2+ binding site (red) and the pore (blue) with ribbon representation of hIP3R-3. Select residues are shown in the sticks. Dashed circles indicate opening through the gate.Full size imageIn addition to IP3, the receptor activation requires Ca2+ at nanomolar concentrations, whereas Ca2+ at higher concentrations is inhibitory, causing the receptor to be tightly regulated by Ca2+,?11,12,13,14,15. The cryo-EM structure of human IP3R-3 (hIP3R-3) in the presence of the inhibitory Ca2+ concentrations (2?mM) revealed two binding sites6. However, their role in channel activation and inhibition has remained uncertain. Furthermore, although ATP binding potentiates the receptor by increasing the open probability and duration of the channel openings, the underlying molecular mechanism has not been uncovered16,17. In this study, we illuminate the structural framework of receptor activation and channel opening by analyzing five cryo-EM structures of hIP3R-3 in the closed-pre-activated, open-activated, and closed-inactivated conformations.Results and discussionCryo-EM structures of hIP3R-3 gating conformationsBimodal regulation of IP3R activity by Ca2+ complicates sample preparation because of the requirement for fine adjustment of Ca2+ concentration to trap the channel in the open conformation. Although free Ca2+ concentrations in solutions can easily be controlled by using Ca2+ buffers such as EGTA or BAPTA, it becomes challenging during sample preparation for cryo-EM due to the small volumes used. Typically, a 2–3?μl protein sample is applied to a cryo-grid, but more than 99% of the sample volume is lost during grid preparation due to extensive blotting with filter paper18. During this time, the samples contact filter paper and cryo-grids, containing various amounts of Ca2+. Small sample volumes and short time frames may reduce these buffers’ efficiency, causing the free Ca2+ concentration to increase to inhibitory levels prior to sample freezing. In order to maximize the chances of obtaining particles in the active state, we prepared the sample in: (1) EDTA, which has ~200 fold faster binding kinetics to Ca2+ than EGTA19, a common Ca2+ chelator, and is more likely to chelate excess Ca2+ and other divalent cations within the short period prior to the sample plunging, (2) ATP, which increases the open probability of IP3Rs and dampens the inhibitory effect of Ca2+,16,17, and (3) high concentrations of IP3.The final hIP3R-3 sample was purified in the presence of 1?mM EDTA and supplemented with 0.5?mM IP3, 5?mM ATP, and 0.1?mM CaCl2 before preparing cryo-grids. Although the free Ca2+ concentration was calculated around 100?nM under these conditions using Maxchelator20, the actual free Ca2+ concentration may be higher due to potential leakage of Ca2+ during the cryo-grid preparation as mentioned above. We performed a cryo-EM analysis on a large dataset by employing exhaustive 3D classification strategies to separate particles belonging to different functional states resulting in five high resolution (3.2–3.8??) structures (Supplementary Figs.?1–6; Supplementary Table?1). The pore region in all structures resolved to 3.5?? or better, allowing us to build side chains and determine if the channel was open or closed (Fig.?1; Supplementary Figs.?2–6).Three structures have closed pores with well-resolved densities for IP3 and ATP and are referred to as pre-active A, B, and C (Fig.?1b; Supplementary Figs.?1–7). The structure named “active” displays drastic conformational changes at the TMD, leading to pore opening (Fig.?1c). In addition to the well-resolved densities for IP3 and ATP, the active structure reveals substantial density, interpreted as Ca2+, at the ARM3-JD interface, referred to as the activatory Ca2+ binding site (Fig.?1c; Supplementary Figs.?5, 7). In the fifth structure, the channel is closed, the activatory Ca2+ binding site is occupied, and the intersubunit interactions of the cytoplasmic domains are lost (Fig.?1d; Supplementary Fig.?6). The structure is highly similar to the hIP3R-3 structures obtained in the presence of inhibitory Ca2+ concentrations6, except for βTF1, which moves closer to the ARM1 (Supplementary Fig.?8). Most notably, ARM2 adopted the same conformation relative to ARM1 and CLD, creating the binding site for the second Ca2+ observed at high Ca2+ concentrations (Supplementary Fig.?8). While these similarities suggest a Ca2+ ion occupies this site and the structure represents the Ca2+ inhibited state, the quality of the map around the region did not allow accurate inspection of the presence of Ca2+ (Supplementary Fig.?8). Therefore, we refer to the structure as “inactive” while it remains unclear if it represents a desensitized state that hIP3R-3 adopts without additional Ca2+ binding or an inhibited state forced by binding of additional Ca2+ to an inhibitory site.It is important to note that our initial 3D classification runs resulted in two major classes grouping the pre-active and active structures into one class and the inactive structure into another (Supplementary Fig.?1). It was essential to perform another round of 3D classification focusing only on the core of the protein to separate the particles in the active state from the pre-active states, potentially due to subtle differences in the overall structures and the much fewer number of particles in the active state (20,039 particles compared to 346,684 particles in the pre-active states) (Supplementary Fig.?1; Supplementary Table?1).Priming of hIP3R-3 for activationTo compare the structures presented here, we aligned their selectivity filters and pore helices (residues 2460-2481), which reside at the luminal side of the TMD and are virtually identical in all classes. The pre-active A structure is almost identical to the previously published IP3-bound hIP3R-3 structure6 (Supplementary Fig.?9a) and reveals that IP3 binding causes the ARM1 to rotate about 23° relative to the βTF-2, causing global conformational changes within the cytoplasmic domains, as observed in previous cryo-EM and X-ray crystallography experiments6,8,21,22,23,24 (Supplementary Fig.?9b, c). The pre-active B and C structures adopt distinct conformations that are intermediates between the pre-active A and open state structures. Based on these conformational changes, we propose a sequential transition from pre-active A to B, then C, although the alternative transitions cannot be ruled out entirely. During the transition to the pre-active B state, the N-terminal domain (NTD) of each protomer comprising βTF1, βTF2, ARM1, ARM2, and CLD rotates about 4° counter-clockwise relative to the TMD and moves about 2?? closer to the membrane plane (Fig.?2a; Supplementary Movie?1). In the pre-active C state, the NTDs remain primarily unchanged compared to the pre-active B state, while the ARM3 and JD are rotated by 7°, causing mild distortions at the cytoplasmic side of the TMD without opening the channel (Fig.?2b; Supplementary Movie?1). Compared to the ligand-free conformation, the βTFs move about 7?? closer to the membrane plane, and ARM3-JD rotates about 11° in the pre-active C conformation.Fig. 2: Conformational changes in the pre-active states.a, b Ribbon representations of hIP3R structures superposed on the residues forming the selectivity filter and P-helix of the TMDs, emphasizing the conformational changes between the states indicated above. Domains with substantial conformational changes are shown in full colors only on one subunit, while the rest of the protein is transparent. Curved and straight red arrows indicate the rotation and translation of the domains with red labels relative to the rotation axis (black bars), respectively.Full size imageCa2+-mediated conformational changes leading to pore openingIn the absence of Ca2+, the ARM3 and JD act as a rigid body, where there are no significant conformational changes relative to each other (Fig.?2a, b). When Ca2+ is bound, the JD rotates about 11° relative to the ARM3 (Fig.?3a), resembling a clamshell closure, which leads to global conformational changes in the whole receptor, including the movement of the NTD closer to the membrane plane by 2?? (Fig.?3b; Supplementary Movie?1). In contrast to the limited rotation of the ARM3 (about 5°), the JD rotates about 14° around an axis roughly perpendicular to the membrane plane, leading to conformational changes at the TMD and resulting in pore opening in the active state (Fig.?3b).Fig. 3: Conformational changes coupling Ca2+ binding to pore opening.a Comparison of the JD (shown in full colors) orientation relative to the ARM3 (shown transparent) in the pre-active-C (orange) and active (blue) structures. The black bar indicates the axis for the rotation of the JD. Ca2+ and ATP are shown as spheres. b Global conformational changes induced by Ca2+ binding are depicted similar to Fig.?2. c Close-up view of the Ca2+ binding site in the active conformation. Domains are colored as in Fig.?1.Full size imageCa2+ is coordinated by E1882 and E1946 on the ARM3 and the main-chain carboxyl group of T2581 on the JD (Fig.?3c). H1884 and Q1949 are also close and may interact with Ca2+ through water molecules (Fig.?3c). These residues are highly conserved in the homologous ion channel family, ryanodine receptors (RyRs), suggesting a common activation mechanism in IP3Rs and RyRs25 (Supplementary Fig.?10a, b). Mutation of the corresponding residues in RyRs markedly reduced the sensitivity to Ca2+, further supporting this site’s involvement in the Ca2+ induced activation26,27,28.ATP binding siteWithin the JD, we observed a well-resolved cryo-EM density for ATP in all the structures (Supplementary Fig.?7). The quality of the maps obtained through local refinement allowed unambiguous modeling of ATP, revealing its key interactions with the protein residues (Fig.?4a, b). The adenosine base intercalates into a cavity surrounded by F2156, F2539, I2559, M2565, and W2566 near the zinc finger motif and forms hydrogen bonds with the sulfur of C2538, the backbone amide group of F2539, and the carbonyl groups of H2563 and I2559 (Fig.?4b). The phosphate moieties interact with K2152, K2560, and N2564 (Fig.?4b). There are no apparent structural changes around the binding site upon ATP binding, suggesting that ATP’s potentiating effect is likely due to the increased rigidity of the JD (Supplementary Fig.?9d). ATP binding site is highly conserved among the subtypes except for E2149 which corresponds to lysine and arginine in IP3R-1 and IP3R-2 (Fig.?4c). A positively charged residue instead of E2149 in the proximity of the phosphate moieties may cause tighter interaction of ATP with IP3R-1 and IP3R-2, explaining the low binding affinity of ATP to IP3R-3 compared to IP3R-1 and IP3R-217.Fig. 4: ATP binds to the JD.a The cryo-EM density of ATP (red mesh) from the composite map of the pre-active A state and the modeled ATP molecule. b Close-up view of the ATP binding site in the pre-active A state. Dashed lines indicate hydrogen bonding. c Sequence alignment of hIP3R subtypes around the residues forming the ATP binding site. Residues shown in (b) are highlighted. Select residues are indicated by arrows, and E2149 is labeled in red.Full size imageATP binds to a similar location near the zinc finger motif in RyRs25,29,30. However, its binding mode differs, potentially due to the differences in the residues that form the binding pocket, most notably the basic residues interacting with the phosphate moieties (Supplementary Fig.?10a, c, d). In RyR-1s, the phosphate moieties interact with K4211, K4214, and R4215, all located on a single helix (Supplementary Fig.?10c, d). In hIP3R-3, there is only a single lysine residue (K2152) on the corresponding helix, and the phosphate moieties interact with K2560, located on the opposite side of the binding pocket. A leucine residue (L4980) occupies this position in RyR-1s. The differences in the number and location of the basic residues likely force the phosphate moieties of ATP to adopt different conformations. Furthermore, F2156 in hIP3R-3 points toward the adenosine binding pocket, prohibiting ATP from adopting the conformations observed in RyR-1s due to steric clash in hIP3R-3s (Supplementary Fig.?10c, d).Structure of the TMD in the open conformationThe TMD of IP3Rs has the same overall architecture of voltage-gated ions channels with a central pore domain, consisting of S5, S6, and pore (P) helix, surrounded by pseudo-voltage-sensor domains (pVSDs), consisting of S1, S2, S3, and S4 helices along with two IP3R/RyR specific TM helices (S1’ and S1”) (Fig.?5). In the closed channel, F2513 and I2517 of the S6 helix form two layers of hydrophobic constriction at the pore, blocking the path for the permeation of hydrated ions (Fig.?5). JD’s rotation upon Ca2+ binding pushes the pVSD’s cytoplasmic side away from the pore domain by about 7?? and tilts the cytoplasmic side of the S6 (S6cyt) by 12° (Fig.?5a; Supplementary Movie?1). Concurrently, the S4-5 linker and S5 helix move away from the S6 helix, thereby inducing a distortion of S6 around the constriction site and moving F2513 and I2517 away from the pore. As a result, the diameter of the water-accessible pore increases to 8??, large enough to permeate hydrated cations (Fig.?5b). The flexibility introduced by the neighboring glycine residue (G2514), mutation of which to alanine in IP3R-1 is associated with spinocerebellar ataxia 29 (SCA29)31, is likely critical to the movement of F2513. The tilting of the S6cyt breaks the salt bridge between D2518 and R2524 of the neighboring subunits, moving D2518 towards the pore while pulling R2524 away, which creates an electronegative path on the cytoplasmic side of the pore (Supplementary Fig.?11). In contrast to the prediction of a π- to α-helix transition at the S6lum during channel opening6,10, the π-helix remains intact, and its tip acts as a pivot for the S6cyt tilting and bulging (Fig.?5).Fig. 5: Structure of the IP3R-3 in the open conformation.a Comparison of the hIP3R-3 structures in the pre-active C and active conformations aligned as in?Fig.?2. b Ion permeation pathways of hIP3R-3 in pre-active C and active conformations (radii coloring: red, <0.8??; green, 0.8-4.0??; gray, >4.0??) along with the 1D graph of the pore radius. The JD and TMD of the active state are shown in cyan and violet, respectively. The pre-active C?structure is colored orange.Full size imageAlthough the TMDs of IP3Rs and RyRs are highly similar, there are noticeable differences in their pore structures (Supplementary Fig.?10e, f). In RyRs, the constriction site is formed by glutamine and isoleucine, corresponding to F2513 and I2517 in hIP3R-3, respectively32. In the open state of RyRs, the isoleucine is positioned similarly to I2517 of hIP3R-325,33,34. On the other hand, the glutamine residue faces the pore in the open state, forming part of the hydrophilic permeation pathway, unlike F2513. Interestingly, N2510 in hIP3R-3, which corresponds to alanine in RyRs, faces the permeation pathway similar to the glutamine of RyRs, suggesting that the amide group plays an important role in the ion permeation. However, since the side chain of N2510 extends from a different position on the S6 helix than the side chain of glutamine in RyRs, the binding pocket for ryanodine25, a RyR-specific inhibitor, is not present in IP3R, potentially causing IP3Rs to be unresponsive to ryanodine32.Several missense mutations identified in the IP3R subtypes are associated with diseases, including spinocereblar ataxia, Gillespie syndrome, anhidrosis, and neck squamous cell carcinoma (Supplementary Fig.?12; reviewed in32,35,36). Perhaps not surprisingly, most of these mutations are localized around the IP3 binding site and alter IP3 binding affinity32,35,36,37. Another hot spot for these mutations is the constriction site of the pore, which undergoes conformational changes during channel opening (Supplementary Fig.?12). It is plausible that these mutations either affect the Ca2+ permeability (e.g., mutation of N251038 or I251739) or restrict conformational changes required for dilation of the pore (e.g., mutation of G251431). Two of the mutated residues (T251940 and F252041) interact with the residues on the S4-S5 linker, which couples the tilting of the pVSD to the bulging of the constriction site (Supplementary Fig.?12b). Mutations of these residues are likely to impair this coupling and thus hinder gating.The flexibility of the CTDThe CTD, extending from the JD along the symmetry axis, forms a left-handed coiled-coil motif before interacting with the βTF2 of the neighboring subunit. The density for the CTD was poorly resolved in all of the states (Supplementary Fig.?13a, b). However, the coiled-coil motifs were visible in the unsharpened maps in the pre-active and active states, enabling us to model poly-alanine peptides without assigned registries (Supplementary Fig.?13a, b). The densities for the extensions from the coiled-coil motif towards the βTF2 become visible when viewed at lower thresholds, whereas the linkers between the JD and the coiled-coil motif remain invisible, indicating higher flexibility for this region (Supplementary Fig.?13a, b). We did not observe any interpretable density for the CTD in the inactive state (Supplementary Fig.?13a, b).For IP3R-1, the CTD was proposed to transmit the conformational changes induced by IP3 at the NTD to the JD8. In IP3R-3, there are no apparent changes on the coiled-coil motif in the pre-active states, but the coiled-coil motif rotates about 20° around the symmetry axis and moves closer to the TMD by 6?? in the active state (Supplementary Fig.?13c, d). However, the linker between the coiled-coil motif and JD remains flexible, suggesting that the structural rearrangements of this domain are not directly enforcing the channel opening (Supplementary Fig.?13). In line with these observations, removing CTD residues interacting with the βTF2 or swapping the C-terminal region of IP3R-1 with the RyRs, which lack the extended CTD, did not diminish receptor activation21,24,42.Mechanism of hIP3R-3 activation and gatingIt has been long recognized that IP3 binding primes the receptor for activation by Ca2+,43, but how the priming is achieved has remained elusive. Our structures reveal that IP3 binding leads to several conformational changes at the NTD, ARM3, and JD, without any apparent structural changes at the activatory Ca2+ binding site, and that the ARM3 and JD adopt a new pre-gating conformation relative to the TMD with modest changes at the intersubunit interface between the JDs at the cytoplasmic side of the TMD (Fig.?6; Supplementary Fig.?14; Supplementary Movie?1). In addition, ARM3s are constrained in their pre-gating conformation by the tetrameric cage-like assembly of the NTDs, forcing the JDs to rotate upon Ca2+ binding. The NTD assembly is maintained by the βTF1-βTF2 intersubunit interactions (βTF ring), which remains intact in the pre-active and active states (Fig.?6; Supplementary Fig.?15; Supplementary Movie?1) and acts as a pivot for the conformational changes that stabilize the ARM3. On the other hand, its disruption in the inactive state leads to the loosening of the tetrameric assembly of the NTDs, relieving the ARM3 constraints and causing the JD and TMD to adopt the closed channel conformation despite the bound Ca2+ to the activatory site. Supporting this hypothesis, the removal of βTF1 or mutation of W168, which resides at the βTF1-βTF2 interface (Supplementary Fig.?15), was shown to abolish IP3R activity44,45.Fig. 6: Schematic representation of the IP3R gating cycle.A side view of the two opposing subunits (left) and cytoplasmic views of the βTFs and ARM3-JD tetramers (right) for each indicated functional state is depicted. The ARM2 and CTD are omitted for clarity. Arrows shown on the domains indicate the direction of the rotation or translation from the previous conformation.Full size imageIn conclusion, the ensemble of structures obtained from the same sample demonstrates structural heterogeneity of IP3Rs in the presence of IP3, ATP, and Ca2+. Our ability to correlate these structures with their plausible functional states allowed us to define the conformational changes at different gating states, revealing the structural features that underpin IP3R activation and gating. These structures will likely serve as foundations for future experiments addressing biophysical and functional questions related to IP3Rs. Furthermore, our study reinforces the power of cryo-EM in analyzing heterogeneous samples and highlights the importance of a thorough investigation of the data to identify physiologically relevant conformations, even when they constitute only a tiny fraction of the sample.MethodsProtein expression and purificationExpression and purification of hIP3R-3 were performed as previously described with minor modifications10. Briefly, hIP3R-3 (residues 4-2671) with a C-terminal OneStrep tag was expressed using the MultiBac expression system46. Sf9 cells (4?×?106 cells/mL) were harvested by centrifugation (4000?×?g) 48?h after infection with the baculovirus. Cells resuspended in a lysis buffer of 200?mM NaCl, 40?mM Tris-HCl pH 8.0, 2?mM EDTA pH 8.0, 10?mM β-mercaptoethanol (BME), and 1?mM Phenylmethylsulfonyl fluoride (PMSF) were lysed using Avastin EmulsiFlex-C3. After centrifugation of the lysate at 7000?×?g for 20?min to remove large debris, the membrane was pelleted by centrifugation at 185,000?×?g (Type Ti45 rotor) for 1?h. Membrane pellets were homogenized in ice-cold resuspension buffer (200?mM NaCl, 40?mM Tris-HCl pH 8.0, 2?mM EDTA pH 8.0, 10?mM BME) using a Dounce homogenizer, and solubilized using 0.5% Lauryl maltose neopentyl glycol (LMNG) and 0.1% glyco-diosgenin (GDN) at a membrane concentration of 100?mg/mL. After 4?h of gentle mixing in the cold room, the insoluble material was pelleted by centrifugation at 185,000?×?g (Type Ti45 rotor) for 1?h, and the supernatant was passed through Strep-XT resin (IBA Biotagnology) via gravity flow. The resin was washed first with 5 column volume (CV) of wash buffer composed of 200?mM NaCl, 20?mM Tris-HCl pH 8.0, 10?mM BME, 0.005% GDN, 0.005% LMNG, followed by 5 CV of wash buffer supplemented with 5?mM ATP and 20?mM MgCl2 to remove any bound chaperone proteins, and finally with 5CV of wash buffer supplemented with 1?mM EDTA. The protein was eluted using wash buffer supplemented with 1?mM EDTA and 100?mM D-Biotin (pH 8.2). The protein was further purified by size exclusion chromatography (SEC) using a Superose 6 Increase column (10/300 GL, GE Healthcare) equilibrated with the SEC buffer composed of 200?mM NaCl, 20?mM Tris-HCl pH 8.0, 1?mM EDTA pH 8.0, 2?mM TCEP, 0.005% LMNG, and 0.005% GDN. The fractions corresponding to hIP3R-3 were combined and concentrated to 4?mg/mL using a 100?kDa centrifugal filter (Sartorius). The concentrated sample was then centrifuged at 260,000?×?g using an S100AT rotor (ThermoFisher Scientific). The concentration dropped to 1.8?mg/mL.Cryo-EM sample preparation and data collectionPurified hIP3R-3 in the SEC buffer containing 1?mM EDTA was supplemented with 500?μM IP3 (from 10?mM stock in water), 0.1?mM CaCl2, and 5?mM ATP (from 100?mM stock, pH 7.2). 2.0?μL of the protein sample was applied to 300 mesh Cu Quantifoil 1.2/1.3 grids (Quantifoil Microtools) that were glow discharged for 20?s at 25?mA. The grids were blotted for 7?s at force 10 using single-layer Whatman ashless filter papers (Cat. #: 1442-055, GE Healthcare) and were plunged into liquid ethane using an FEI MarkIV Vitrobot at 8?°C and 100% humidity. The filter papers were not pre-treated with Ca2+ chelators or any other chemicals. Four grids prepared using the same sample were imaged using a 300?kV FEI Krios G3i microscope equipped with a Gatan K3 direct electron camera in four different data collection sessions at Case Western Reserve University. Movies containing 40–50 frames were collected at a magnification of ×105,000 in super-resolution mode with a physical pixel size of 0.828??/pixel and defocus values at a range of ?0.8 to ?1.6?μm using the automated imaging software SerialEM47 and EPU (ThermoFisher Scientific).Cryo-EM data processingDatasets from four sessions were initially processed separately using Relion 3.048. We used MotionCor249 and Gtcf50 to perform beam-induced motion correction and CTF estimations, respectively. We performed auto picking using the Laplacian-of-Gaussian option of Relion, extracted particles binned 4?×?4, and performed 2D class classification. Using the class averages with apparent features, we performed another round of particle picking. We cleaned the particles, extracted as 4?×?4 binned, through 2D classification and performed 3D classification using the hIP3R-3 map (EMD-2084910), which was converted to the appropriate box and pixel size. We observed two predominant conformations. One had a compact NTD and tight interactions between subunits as in previously published IP3R structures in the absence of Ca2+, hereafter called “compact” conformation6,7,8,10 (Supplementary Fig.?1). The other one had the NTD of each subunit tilted away from the central symmetry axis resembling hIP3R-3 structures obtained in the presence of high Ca2+ concentrations, hereafter called “l(fā)oose” conformation6 (Supplementary Fig.?1). These particles were separately selected and reextracted using a box size of 480?×?480 pixels at the physical pixel size. After 3D refinements, we performed CTF refinement and Bayesian polishing51.We combined all the polished particles and performed another round of 3D classification, using one of the compact structures as a reference map. We grouped particles into “compact” and “l(fā)oose” classes (Supplementary Fig.?1). Refinement of the particles in the “compact” conformation yielded a 3D reconstruction with an average resolution of 3.9??. Although there were slight changes at the TMD compared to the structure in the closed state, these changes were not significant enough to suggest that the channel was open. To more clearly resolve the density around the TMD, we performed another round of 3D classification using a mask that only covers the ARM3, JD, and TMD and without performing an angular or translational alignment in Relion3 (Supplementary Fig.?1)52. 3D refinements of the particles in each class were performed using non-uniform refinement in CryoSPARC, enforcing C4 symmetry and local CTF refinements (Supplementary Fig.?1)53. Five classes led to four high-resolution (better than 4??) 3D reconstructions, whereas the 3D refinement of the other three classes resulted in poorly resolved maps. The particles in the “l(fā)oose” conformation were processed using non-uniform refinement in CryoSPARC, but without enforcing any symmetry. Local resolution estimates were calculated using CryoSPARC53 (Supplementary Figs.?2–6). Some of the data processing and refinement software was supported by SBGrid54.To improve the quality of the maps, we performed local refinements using masks covering parts of the original cryo-EM maps (Supplementary Figs.?2–6). We prepared five masks that cover distinct domains of one of the subunits for the pre-active A, B, C, and active conformations. After symmetry expansion using C4 symmetry, we performed local refinement using CryoSparc (Supplementary Figs.?2–5). For the inactive state, we prepared four masks that cover the cytoplasmic domains of each subunit and another mask that covers the tetrameric ARM3, JD, and TMD (Supplementary Fig.?6). The local refinements were performed using C1 symmetry for the cytoplasmic domains and C4 symmetry for the tetrameric ARM3, JD, and TMD. The resulting local refinement maps were aligned onto the original maps using Chimera55 and merged using the “VOP maximum” command of Chimera55 to prepare the composite maps (Supplementary Figs.?2–6).Model buildingModel building was performed using Coot56. We first placed the hIP3R-3 structure in ligand-free conformations (PDB ID: 6UQK10) into the composite map of Pre-active A, and performed rigid-body fitting of individual domains of one of the protomers. We then manually fit the residues into the density and expanded the protomer structure into a tetramer using the C4 symmetry. We performed real-space refinement using Phenix57. We repeated build-refine iterations till a satisfactory model was obtained. This model was used as a starting model for the other structures following the same workflow. Regions without interpretable densities were not built into the model. Residues without apparent density for their side chains were built without their side chains (i.e., as alanines) while maintaining their correct labeling for the amino acid type. The coiled-coil regions were modeled as poly-alanines without residue assignment using the unsharpened maps. Validations of the structural models were performed using MolProbity58 implemented in Phenix57.Figure preparationFigures were prepared using Chimera55, ChimeraX59, and The PyMOL Molecular Graphics System (Version 2.0, Schr?dinger, LLC). Calculation of the pore radii was performed using the software HOLE60.Reporting summaryFurther information on research design is available in the?Nature Research Reporting Summary linked to this article.
Data availability
The data that support this study are available from the corresponding author upon reasonable request. Cryo-EM maps and atomic coordinates are deposited to the Electron Microscopy Data Bank (EMDB) and Protein Data Bank (PDB) databases, respectively. The accession codes are EMD-25667 and 7T3P for pre-active A, EMD-25668 and 7T3Q for pre-active B, EMD-25669 and 7T3R for pre-active C, EMD-25670 and 7T3T for active, and EMD-25671 and 7T3U for inactive states, respectively. The following previously published datasets were used: EMD-20849, Cryo-EM structure of type 3 IP3 receptor revealing presence of a self-binding peptide10. 6UQK, Cryo-EM structure of type 3 IP3 receptor revealing presence of a self-binding peptide10. 6DRC, High IP3 Ca2+ human type 3 1,4,5-inositol trisphosphate receptor6. 6DQV Class 2 IP3-bound human type 3 1,4,5-inositol trisphosphate receptor6. 5TAL, Structure of rabbit RyR1 (Caffeine/ATP/Ca2+ dataset, class 1 and 2)25. 7M6A, High resolution structure of the membrane embedded skeletal muscle ryanodine receptor29. Reagents and other materials will be available upon request from E.K. with a completed materials transfer agreement.
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Download referencesAcknowledgementsWe thank Dr. Kunpeng Lee for cryo-EM data collection at Case Western Reserve University. We thank Theo Humphries and other support staff at the Pacific Northwest Center for Cryo-EM (PNCC), Drs. Elad Binshtein, Melissa Chambers, and Scott Collier at the Cryo-EM facility at Vanderbilt University for their assistance with cryo-EM sample screening. We thank Drs. Hassane Mchaourab, Terunaga Nakagawa, and Silvia Ravera for discussions and review of the manuscript. This work was conducted in part using the CPU and GPU resources of the Advanced Computing Center for Research and Education (ACCRE) at Vanderbilt University. We used the DORS storage system supported by the U.S. National Institute of Health (NIH) (S10RR031634 to Jarrod Smith). This work was supported by the NIH (R01GM141251 to E.K.), Vanderbilt University, Vanderbilt Diabetes and Research Training Center (NIH P30DK020593 to E.K.), and the Molecular Biophysics Training Program (NIH T32GM008320 to E.A.S.).Author informationAuthor notesThese authors contributed equally: Emily A. Schmitz, Hirohide Takahashi.Authors and AffiliationsDepartment of Molecular Physiology and Biophysics, Vanderbilt University, School of Medicine, Nashville, TN, 37232, USAEmily A. Schmitz,?Hirohide Takahashi?&?Erkan KarakasCenter for Structural Biology, Vanderbilt University, Nashville, TN, 37232, USAEmily A. Schmitz,?Hirohide Takahashi?&?Erkan KarakasAuthorsEmily A. SchmitzView author publicationsYou can also search for this author in
PubMed?Google ScholarHirohide TakahashiView author publicationsYou can also search for this author in
PubMed?Google ScholarErkan KarakasView author publicationsYou can also search for this author in
PubMed?Google ScholarContributionsE.K. conceived the project and performed cryo-EM data analysis; E.A.S. optimized and performed protein expression and purification; H.T. performed grid preparation for cryo-EM. All authors contributed to the preparation of the manuscript.Corresponding authorCorrespondence to
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Reprints and permissionsAbout this articleCite this articleSchmitz, E.A., Takahashi, H. & Karakas, E. Structural basis for activation and gating of IP3 receptors.
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