美国斯坦福大学医学院Georgios Skiniotis和Brian K. Kobilka课题组宣布他们确定了神经降压素受体1–G_i1复合物的构象转变。2019年8月1日出版的《自然》发表了这项成果。

研究组提出了人类NTSR1的结构，与激动剂JMV449和异源三聚体G_i1蛋白复合，解析度为3埃。课题组确定了两种构象：一种是规范状态复合物，与最近报道的GPCRG_i/o复合物相似（其中核苷酸结合口袋采用更灵活的构象，可促进核苷酸交换），另一种是G蛋白的非规范状态，相对于受体旋转约45度，并显示出更严格的核苷酸结合口袋。在非正则态下，NTSR1表现出活性构象和非活性构象的特征，说明该结构可能是G蛋白活化途径上的一种中间形式。这一结构信息，辅以分子动力学模拟和功能研究，提供了深入了解G蛋白活化复杂过程的新见解。

研究人员表示，神经降压素受体1（NTSR1）是G蛋白偶联受体（GPCR），其参与G蛋白的多种亚型，并参与对血压、体温、体重及对疼痛的反应的调节。

附：英文原文

Title: Conformational transitions of a neurotensin receptor 1–G i1  complex

Author: Hideaki E. Kato, Yan Zhang, Hongli Hu, Carl-Mikael Suomivuori, Francois Marie Ngako Kadji, Junken Aoki, Kaavya Krishna Kumar, Rasmus Fonseca, Daniel Hilger, Weijiao Huang, Naomi R. Latorraca, Asuka Inoue, Ron O. Dror, Brian K. Kobilka, Georgios Skiniotis

Issue&Volume: Volume 572 Issue 7767

Abstract: Neurotensin receptor 1 (NTSR1) is a G-protein-coupled receptor (GPCR) that engages multiple subtypes of G protein, and is involved in the regulation of blood pressure, body temperature, weight and the response to pain. Here we present structures of human NTSR1 in complex with the agonist JMV449 and the heterotrimeric Gi1 protein, at a resolution of 3Å. We identify two conformations: a canonical-state complex that is similar to recently reported GPCRGi/o complexes (in which the nucleotide-binding pocket adopts more flexible conformations that may facilitate nucleotide exchange), and a non-canonical state in which the G protein is rotated by about 45 degrees relative to the receptor and exhibits a more rigid nucleotide-binding pocket. In the non-canonical state, NTSR1 exhibits features of both active and inactive conformations, which suggests that the structure may represent an intermediate form along the activation pathway of G proteins. This structural information, complemented by molecular dynamics simulations and functional studies, provides insights into the complex process of G-protein activation.

DOI: 10.1038/s41586-019-1337-6

Source:https://www.nature.com/articles/s41586-019-1337-6