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GPBAR活化和胆汁酸识别的结构基础获解析
2020-07-25 12:56

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。

研究人员报道了GPBAR-Gs复合物的冷冻电镜结构,这一复合物被高亲和力P395或半合成胆汁酸衍生物INT-777稳定在3Å分辨率下。这些结构揭示了一个椭圆形的大口袋,内有几个极性基团,可以容纳胆汁酸的两亲性胆酸核心;关键残基的指纹识别正构位点中的各种胆汁酸;推定的第二个胆汁酸结合位点,具有变构特性,并且有助于偏好特性的结构特征。
 
此外,GPBAR具有非典型的激活和G蛋白偶联模式,其特征是将配体结合口袋与Gs偶联位点连接的一组关键残基,以及位于细胞内环3中的特定相互作用基序。
 
总体而言,这项研究不仅揭示了参与了胆汁酸的识别和变构作用的GPBAR独特结构特征,也暗示了GPCR超家族中配体结合口袋和G蛋白结合位点之间存在独特的连接机制。
 
据悉,G蛋白偶联的胆汁酸受体传递多种胆汁酸的跨膜信号,并且是肝-胆汁酸-微生物-代谢轴的信号枢纽。
 
附:英文原文

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

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