美国斯坦福大学Georgios Skiniotis小组揭示Ca²⁺传感受体的异构调节和G蛋白选择性。相关论文于2024年2月7日在线发表于国际学术期刊《自然》。

研究人员使用冷冻电镜和功能测定法研究了嵌入脂质纳米盘中的人类钙传感受体（CaSR）的活化及其与功能性G_i蛋白和G_q蛋白的结合，以及在有或没有钙化药物西那卡西特的情况下的活化。高分辨率结构显示，G_i和G_q驱动活化的CaSR二聚体发生额外的构象变化，以稳定七跨膜结构域（7TM）更广泛的不对称界面，其中涉及关键的蛋白-脂质相互作用。受体的选择性G_i和G_q耦合是通过胞内环和C末端的大量重排实现的，这些重排对两种G蛋白亚型的结合有不同的作用，从而形成了不同的CaSR-G-蛋白界面。这些

结构还揭示了天然多胺以CaSR上的多个位点为目标，通过将带负电荷的区域连接到两个原体之间来增强受体的激活。此外，研究人员还发现氨基酸L-色氨酸（CaSR细胞外结构域的一种著名配体）占据了G蛋白偶联原体的7TM束，与西那卡西酮和其他异位调节剂占据了相同的位置。这些结果为CaSR的G蛋白激活和选择性提供了一个框架，也为CaSR受内源性和非内源性配体的异构调节提供了一个框架。

据介绍，CaSR是一种C族G蛋白偶联受体（GPCR），在调节全身钙平衡中发挥着核心作用。

附：英文原文

Title: Allosteric modulation and G-protein selectivity of the Ca2+-sensing receptor

Author: He, Feng, Wu, Cheng-Guo, Gao, Yang, Rahman, Sabrina N., Zaoralov, Magda, Papasergi-Scott, Makaa M., Gu, Ting-Jia, Robertson, Michael J., Seven, Alpay B., Li, Lingjun, Mathiesen, Jesper M., Skiniotis, Georgios

Issue&Volume: 2024-02-07

Abstract: The calcium-sensing receptor (CaSR) is a family C G-protein-coupled receptor1 (GPCR) that has a central role in regulating systemic calcium homeostasis2,3. Here we use cryo-electron microscopy and functional assays to investigate the activation of human CaSR embedded in lipid nanodiscs and its coupling to functional Gi versus Gq proteins in the presence and absence of the calcimimetic drug cinacalcet. High-resolution structures show that both Gi and Gq drive additional conformational changes in the activated CaSR dimer to stabilize a more extensive asymmetric interface of the seven-transmembrane domain (7TM) that involves key protein–lipid interactions. Selective Gi and Gq coupling by the receptor is achieved through substantial rearrangements of intracellular loop2 and the Cterminus, which contribute differentially towards the binding of the two G-protein subtypes, resulting in distinct CaSR–G-protein interfaces. The structures also reveal that natural polyamines target multiple sites on CaSR to enhance receptor activation by zipping negatively charged regions between two protomers. Furthermore, we find that the amino acid L-tryptophan, a well-known ligand of CaSR extracellular domains, occupies the 7TM bundle of the G-protein-coupled protomer at the same location as cinacalcet and other allosteric modulators. Together, these results provide a framework for G-protein activation and selectivity by CaSR, as well as its allosteric modulation by endogenous and exogenous ligands.

DOI: 10.1038/s41586-024-07055-2

Source: https://www.nature.com/articles/s41586-024-07055-2