小柯机器人

近日，美国斯坦福大学Georgios Skiniotis、丹麦哥本哈根大学Jesper M. Mathiesen等研究人员合作揭示钙敏感受体同源二聚体的不对称激活。2021年6月30日，《自然》杂志在线发表了这项成果。

据研究人员介绍，钙敏感受体（CaSR）是Ca²⁺的细胞表面传感器，是人体钙稳态的主要调节器，也是拟钙药物治疗甲状旁腺疾病的靶点。CaSR是一种C家族G蛋白偶联受体2，可作为专性同源二聚体发挥作用，每个原聚体由Ca²⁺结合胞外域和激活异源三聚体G蛋白的七跨膜螺旋域（7TM）组成。

研究人员报道了与Ca²⁺和各种溶钙或拟钙药物分子结合的、处于非活性或活性状态的近全长人类CaSR冷冻电镜结构。结果表明，在激活后，CaSR同源二聚体采用不对称7TM构象，这为G蛋白偶联活化了一个原聚体。这种不对称性通过在两个原聚体中采用明显不同构象的7TM靶向拟钙剂药物来稳定，而溶解钙质药物的结合将CaSR 7TM锁定在非活性对称构型中。这些结果为CaSR激活提供了详细的结构框架，并为靶向该受体治疗药物的合理设计提供了一个详细的结构框架。

附：英文原文

Title: Asymmetric activation of the calcium-sensing receptor homodimer

Author: Yang Gao, Michael J. Robertson, Sabrina N. Rahman, Alpay B. Seven, Chensong Zhang, Justin G. Meyerowitz, Ouliana Panova, Fadil M. Hannan, Rajesh V. Thakker, Hans Bruner-Osborne, Jesper M. Mathiesen, Georgios Skiniotis

Issue&Volume: 2021-06-30

Abstract: The calcium-sensing receptor (CaSR), a cell-surface sensor for Ca2+, is the master regulator of calcium homeostasis in humans and is the target of calcimimetic drugs for the treatment of parathyroid disorders1. CaSR is a family C G-protein-coupled receptor2 that functions as an obligate homodimer, with each protomer composed of a Ca2+-binding extracellular domain and a seven-transmembrane-helix domain (7TM) that activates heterotrimeric G proteins. Here we present cryo-electron microscopy structures of near-full-length human CaSR in inactive or active states bound to Ca2+ and various calcilytic or calcimimetic drug molecules. We show that, upon activation, the CaSR homodimer adopts an asymmetric 7TM configuration that primes one protomer for G-protein coupling. This asymmetry is stabilized by 7TM-targeting calcimimetic drugs adopting distinctly different poses in the two protomers, whereas the binding of a calcilytic drug locks CaSR 7TMs in an inactive symmetric configuration. These results provide a detailed structural framework for CaSR activation and the rational design of therapeutics targeting this receptor.

DOI: 10.1038/s41586-021-03691-0

Source: https://www.nature.com/articles/s41586-021-03691-0

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
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