Structural mechanism of cooperative activation of the human calcium-sensing receptor by Ca(2+) ions and L-tryptophan.
Structural mechanism of cooperative activation of the human calcium-sensing receptor by Ca(2+) ions and L-tryptophan.
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Ca离子和L-色氨酸协同激活人钙敏感受体的结构机制
DOI：
10.1038/s41422-021-00474-0
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发表时间：
2021-04
期刊：
影响因子：
44.1
通讯作者：
Tian C
中科院分区：
文献类型：
--
作者：
Ling S;Shi P;Liu S;Meng X;Zhou Y;Sun W;Chang S;Zhang X;Zhang L;Shi C;Sun D;Liu L;Tian C
人钙敏感受体（CaSR）是一种C类G蛋白偶联受体（GPCR），负责维持血液中的Ca 2+稳态。一般的共识是细胞外Ca 2+是CaSR的主要激动剂。脂肪族和芳香族L-氨基酸，如L-Phe和L-Trp，增加CaSR对Ca 2+的敏感性，被认为是变构激活剂。CaSR二聚体的胞外结构域（ECD）的晶体结构已经证明了Ca 2+和L-Trp结合位点以及在Ca 2 +/L-Trp结合时ECD的构象变化。然而，在结构水平上，Ca 2 +/L-Trp与ECD的结合如何导致跨膜结构域（TMD）的构象变化以及随后的CaSR活化仍有待理解。在这里，我们确定了全长人CaSR的结构在非活性状态，Ca 2+或L-Trp结合状态，和Ca 2 +/L-Trp结合的活性状态，使用单粒子冷冻电子显微镜。结构研究表明，L-Trp结合诱导CaSR的捕蝇草（VFT）结构域关闭，使受体进入中间活性状态。Ca 2+结合将VFT结构域的构象变化传递到TMDs，从而诱导二聚体CaSR的两个TMDs之间的紧密接触，激活受体。重要的是，我们的结构和功能研究表明，Ca 2+离子和L-Trp协同激活CaSR。氨基酸不能单独激活CaSR，但可以在Ca 2+存在下促进受体激活。我们的数据为C类GPCR的激活提供了补充性见解，并可能有助于开发靶向CaSR的新药。
The human calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor (GPCR) responsible for maintaining Ca2+ homeostasis in the blood. The general consensus is that extracellular Ca2+ is the principal agonist of CaSR. Aliphatic and aromatic L-amino acids, such as L-Phe and L-Trp, increase the sensitivity of CaSR towards Ca2+ and are considered allosteric activators. Crystal structures of the extracellular domain (ECD) of CaSR dimer have demonstrated Ca2+ and L-Trp binding sites and conformational changes of the ECD upon Ca2+/L-Trp binding. However, it remains to be understood at the structural level how Ca2+/L-Trp binding to the ECD leads to conformational changes in transmembrane domains (TMDs) and consequent CaSR activation. Here, we determined the structures of full-length human CaSR in the inactive state, Ca2+- or L-Trp-bound states, and Ca2+/L-Trp-bound active state using single-particle cryo-electron microscopy. Structural studies demonstrate that L-Trp binding induces the closure of the Venus flytrap (VFT) domain of CaSR, bringing the receptor into an intermediate active state. Ca2+ binding relays the conformational changes from the VFT domains to the TMDs, consequently inducing close contact between the two TMDs of dimeric CaSR, activating the receptor. Importantly, our structural and functional studies reveal that Ca2+ ions and L-Trp activate CaSR cooperatively. Amino acids are not able to activate CaSR alone, but can promote the receptor activation in the presence of Ca2+. Our data provide complementary insights into the activation of class C GPCRs and may aid in the development of novel drugs targeting CaSR.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
16.8
作者：
Kniazeff, J;Bessis, AS;Pin, JP
通讯作者：
Pin, JP
DOI：
10.1107/s2059798318009324
发表时间：
2018-09-01
期刊：
Acta crystallographica. Section D, Structural biology
影响因子：
--
作者：
Afonine PV;Klaholz BP;Moriarty NW;Poon BK;Sobolev OV;Terwilliger TC;Adams PD;Urzhumtsev A
通讯作者：
Urzhumtsev A
影响因子：
4.7
作者：
Frangaj A;Fan QR
通讯作者：
Fan QR
影响因子：
48
作者：
Kucukelbir, Alp;Sigworth, Fred J.;Tagare, Hemant D.
通讯作者：
Tagare, Hemant D.