小柯机器人

中国科学院上海药物研究所徐华强等研究人员合作揭示一个偏向细胞内激动剂介导的GPCR激活和GRK2组装。2023年8月2日，《自然》杂志在线发表了该论文。

研究人员表示，GPCR激酶（GRK）对G蛋白偶联受体（GPCR）的磷酸化可使G蛋白信号脱敏并促进阻遏蛋白信号，而阻遏蛋白信号也受偏向配体的调节。由于GPCR与GRK的相互作用较弱，GRK在GPCR上的分子组装以及GRK介导的偏向性信号传导的基础在很大程度上仍不为人所知。

研究人员报告了神经营养素受体1（NTSR1）与GRK2、Gα_q和阻遏蛋白偏倚配体SBI-5537结合的复合结构。密度图显示了完整的GRK2与受体的排列，GRK2的N端螺旋与受体跨膜螺旋6向外运动形成的开放的胞质袋对接，类似于G蛋白与受体的结合。SBI-553与GRK2和NTSR1之间的界面结合，增强GRK2的结合。SBI-553的结合模式与阻遏蛋白结合相容，但却与Gα_q蛋白的结合相冲突，从而为其与阻遏蛋白偏重的信号能力提供了一种机制。总之，这些结构为理解GPCR-GRK相互作用和GRK2介导的偏向信号传导的细节提供了一个合理的模型。

附：英文原文

Title: GPCR activation and GRK2 assembly by a biased intracellular agonist

Author: Duan, Jia, Liu, Heng, Zhao, Fenghui, Yuan, Qingning, Ji, Yujie, Cai, Xiaoqing, He, Xinheng, Li, Xinzhu, Li, Junrui, Wu, Kai, Gao, Tianyu, Zhu, Shengnan, Lin, Shi, Wang, Ming-Wei, Cheng, Xi, Yin, Wanchao, Jiang, Yi, Yang, Dehua, Xu, H. Eric

Issue&Volume: 2023-08-02

Abstract: Phosphorylation of G-protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) desensitizes G-protein signalling and promotes arrestin signalling, which is also modulated by biased ligands1,2,3,4,5,6. The molecular assembly of GRKs on GPCRs and the basis of GRK-mediated biased signalling remain largely unknown owing to the weak GPCR–GRK interactions. Here we report the complex structure of neurotensin receptor 1 (NTSR1) bound to GRK2, Gαq and the arrestin-biased ligand SBI-5537. The density map reveals the arrangement of the intact GRK2 with the receptor, with the N-terminal helix of GRK2 docking into the open cytoplasmic pocket formed by the outward movement of the receptor transmembrane helix 6, analogous to the binding of the G protein to the receptor. SBI-553 binds at the interface between GRK2 and NTSR1 to enhance GRK2 binding. The binding mode of SBI-553 is compatible with arrestin binding but clashes with the binding of Gαq protein, thus providing a mechanism for its arrestin-biased signalling capability. In sum, our structure provides a rational model for understanding the details of GPCR–GRK interactions and GRK2-mediated biased signalling.

DOI: 10.1038/s41586-023-06395-9

Source: https://www.nature.com/articles/s41586-023-06395-9

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/
投稿链接：http://www.nature.com/authors/submit_manuscript.html