Structural basis of GPBAR activation and bile acid recognition

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 () and Yan Zhang ()
Additional contact information
Fan Yang: Shandong University
Chunyou Mao: Zhejiang University School of Medicine
Lulu Guo: Shandong University
Jingyu Lin: Shandong University
Qianqian Ming: Zhejiang University School of Medicine
Peng Xiao: Shandong University
Xiang Wu: Shandong University
Qingya Shen: Zhejiang University School of Medicine
Shimeng Guo: Chinese Academy of Sciences
Dan-Dan Shen: Zhejiang University School of Medicine
Ruirui Lu: Shandong University
Linqi Zhang: Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education
Shenming Huang: Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education
Yuqi Ping: Shandong University
Chenlu Zhang: Chinese Academy of Sciences
Cheng Ma: Zhejiang University School of Medicine
Kai Zhang: Shandong University
Xiaoying Liang: Chinese Academy of Sciences
Yuemao Shen: Shandong University
Fajun Nan: Chinese Academy of Sciences
Fan Yi: Shandong University
Vincent C. Luca: Moffitt Cancer Center and Research Institute
Jiuyao Zhou: Guangzhou University of Chinese Medicine
Changtao Jiang: Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education
Jin-Peng Sun: Shandong University
Xin Xie: Chinese Academy of Sciences
Xiao Yu: Shandong University
Yan Zhang: Zhejiang University School of Medicine

Nature, 2020, vol. 587, issue 7834, 499-504

Abstract: Abstract The G-protein-coupled bile acid receptor (GPBAR) conveys the cross-membrane signalling of a vast variety of bile acids and is a signalling hub in the liver–bile acid–microbiota–metabolism axis1–3. Here we report the cryo-electron microscopy structures of GPBAR–Gs complexes stabilized by either the high-affinity P3954 or the semisynthesized bile acid derivative INT-7771,3 at 3 Å resolution. These structures revealed a large oval pocket that contains 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 that contribute to bias properties. Moreover, GPBAR undertakes an atypical mode of activation and G protein coupling that features a different set of key residues connecting the ligand-binding pocket to the Gs-coupling site, and a specific interaction motif that is localized in intracellular loop 3. Overall, our study not only reveals unique structural features of GPBAR that are 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 G-protein-coupled receptor superfamily.

Date: 2020
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DOI: 10.1038/s41586-020-2569-1

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