浙江大学Yan Zhang等研究人员合作揭示出G蛋白偶联的胆汁酸受体(GPBAR)活化和胆汁酸识别的结构基础。相关论文于2020年7月22日在线发表在《自然》杂志上。
Title: Structural basis of GPBAR activation and bile acid recognition
Author: Fan Yang, Chunyou Mao, Lulu Guo, Jingyu Lin, Qianqian Ming, Peng Xiao, Xiang Wu, Qingya Shen, Shimeng Guo, Dan-Dan Shen, Ruirui Lu, Linqi Zhang, Shenming Huang, Yuqi Ping, Chenlu Zhang, Cheng Ma, Kai Zhang, Xiaoying Liang, Yuemao Shen, Fajun Nan, Fan Yi, Vincent C. Luca, Jiuyao Zhou, Changtao Jiang, Jin-Peng Sun, Xin Xie, Xiao Yu, Yan Zhang
Issue&Volume: 2020-07-22
Abstract: The G protein-coupled bile acid receptor (GPBAR) conveys the cross-membrane signaling of a vast variety of bile acids and is a signaling hub in the liver–bile-acid–microbiota–metabolism axis1–3. Here, we report the cryo-EM structures of GPBAR–Gs complexes stabilized by either the high-affinity P3954 or the semisynthesized bile acid derivative INT-7771,3 at 3- resolution. These structures revealed a large oval-shaped pocket containing several polar groups positioned to accommodate the amphipathic cholic core of bile acids, a fingerprint of key residues to recognize diverse bile acids in the orthosteric site, a putative second bile acid binding site with allosteric properties and structural features contributing to bias properties. Moreover, GPBAR undertakes an atypical mode of activation and G-protein coupling featuring a different set of key residues connecting the ligand binding pocket to the Gs coupling site, and a specific interaction motif localized in intracellular loop 3. Overall, our study not only reveals unique structural features of GPBAR involved in bile acid recognition and allosteric effects, but also suggests the presence of distinct connecting mechanisms between the ligand binding pocket and the G protein binding site in the GPCR superfamily.
DOI: 10.1038/s41586-020-2569-1
Source: https://www.nature.com/articles/s41586-020-2569-1
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
本期文章:《自然》:Online/在线发表