Author
Listed:
- Fan Yang
(Shandong University
Shandong University)
- Chunyou Mao
(Zhejiang University School of Medicine
Zhejiang University Medical Center)
- Lulu Guo
(Shandong University
Shandong University)
- Jingyu Lin
(Shandong University
Shandong University)
- Qianqian Ming
(Zhejiang University School of Medicine
Zhejiang University Medical Center
Moffitt Cancer Center and Research Institute)
- Peng Xiao
(Shandong University)
- Xiang Wu
(Shandong University)
- Qingya Shen
(Zhejiang University School of Medicine
Zhejiang University Medical Center)
- Shimeng Guo
(Chinese Academy of Sciences)
- Dan-Dan Shen
(Zhejiang University School of Medicine
Zhejiang University Medical Center)
- Ruirui Lu
(Shandong University
Guangzhou University of Chinese Medicine)
- 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
University of 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
Guangzhou University of Chinese Medicine
Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education)
- Xin Xie
(Chinese Academy of Sciences
University of Chinese Academy of Sciences)
- Xiao Yu
(Shandong University
Shandong University)
- Yan Zhang
(Zhejiang University School of Medicine
Zhejiang University Medical Center
Zhejiang University School of Medicine)
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.
Suggested Citation
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 &, 2020.
"Structural basis of GPBAR activation and bile acid recognition,"
Nature, Nature, vol. 587(7834), pages 499-504, November.
Handle:
RePEc:nat:nature:v:587:y:2020:i:7834:d:10.1038_s41586-020-2569-1
DOI: 10.1038/s41586-020-2569-1
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Cited by:
- Wessel A. C. Burger & Vi Pham & Ziva Vuckovic & Alexander S. Powers & Jesse I. Mobbs & Yianni Laloudakis & Alisa Glukhova & Denise Wootten & Andrew B. Tobin & Patrick M. Sexton & Steven M. Paul & Chri, 2023.
"Xanomeline displays concomitant orthosteric and allosteric binding modes at the M4 mAChR,"
Nature Communications, Nature, vol. 14(1), pages 1-11, December.
- Geng Chen & Jun Xu & Asuka Inoue & Maximilian F. Schmidt & Chen Bai & Qiuyuan Lu & Peter Gmeiner & Zheng Liu & Yang Du, 2022.
"Activation and allosteric regulation of the orphan GPR88-Gi1 signaling complex,"
Nature Communications, Nature, vol. 13(1), pages 1-12, December.
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