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Structural basis of GPBAR activation and bile acid recognition

文献类型：期刊论文

作者Yang, Fan1,5; Mao, Chunyou2,3,4; Guo, Lulu1,5; Lin, Jingyu1,5; Ming, Qianqian2,3,4,11; Xiao, Peng1; Wu, Xiang1; Shen, Qingya2,3,4; Guo, Shimeng6; Shen, Dan-Dan2,3,4
刊名NATURE
出版日期2020-07-22
页码29
ISSN号0028-0836
DOI10.1038/s41586-020-2569-1
通讯作者Sun, Jin-Peng(sunjinpeng@sdu.edu.cn) ; Xie, Xin(xxie@simm.ac.cn) ; Yu, Xiao(yuxiao@sdu.edu.cn) ; Zhang, Yan(zhang_yan@zju.edu.cn)
英文摘要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 axis(1-3). Here we report the cryo-electron microscopy structures of GPBAR-G(s)complexes stabilized by either the high-affinity P395(4)or the semisynthesized bile acid derivative INT-777(1,3)at 3 angstrom 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 G(s)-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. Using cryo-electron microscopy, the authors report the structures of G-protein-coupled bile acid receptor-G(s)complexes and reveal the structural basis of bile acid recognition.
WOS关键词CRYO-EM STRUCTURE ; RECEPTOR ; MUTANT ; TGR5 ; VISUALIZATION ; VALIDATION ; INSIGHTS ; TOOLS ; MAPS
资助项目National Key R&D Program of China[2018YFC1003600] ; National Key R&D Program of China[2019YFA050880] ; National Science Fund for Excellent Young Scholars[81822008] ; National Science Fund for Excellent Young Scholars[81922071] ; National Science Fund for Distinguished Young Scholars[81773704] ; National Science Fund for Distinguished Young Scholars[81425024] ; National Science Fund for Distinguished Young Scholars[81525005] ; Zhejiang Province National Science Fund for Excellent Young Scholars[LR19H310001] ; National Natural Science Foundation of China[31900936] ; National Natural Science Foundation of China[31700692] ; National Natural Science Foundation of China[81730099] ; China Postdoctoral Science Foundation[2019T120587] ; Innovative Research Team in University[IRT_17R68] ; Protein Facility, Zhejiang University School of Medicine
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:000580948000001
出版者NATURE RESEARCH
源URL[http://119.78.100.183/handle/2S10ELR8/291463]  
专题中国科学院上海药物研究所
通讯作者Sun, Jin-Peng; Xie, Xin; Yu, Xiao; Zhang, Yan
作者单位1.Shandong Univ, Key Lab Expt Teratol, Minist Educ, Dept Biochem & Mol Biol,Sch Basic Med Sci,Cheeloo, Jinan, Peoples R China
2.Zhejiang Univ, Sch Med, Dept Pathol, Sir Run Run Shaw Hosp, Hangzhou, Peoples R China
3.Zhejiang Univ, Sch Med, Dept Biophys, Hangzhou, Peoples R China
4.Zhejiang Univ, Med Ctr, Zhejiang Lab Syst & Precis Med, Hangzhou, Peoples R China
5.Shandong Univ, Key Lab Expt Teratol, Minist Educ, Dept Physiol,Sch Basic Med Sci, Jinan, Peoples R China
6.Chinese Acad Sci, CAS Key Lab Receptor Res, Natl Ctr Drug Screening, Shanghai Inst Mat Med, Shanghai, Peoples R China
7.Guangzhou Univ Chinese Med, Dept Pharmacol, Sch Pharmaceut Sci, Guangzhou, Peoples R China
8.Peking Univ, Key Lab Mol Cardiovasc Sci, Minist Educ, Dept Physiol & Pathophysiol,Sch Basic Med Sci, Beijing, Peoples R China
9.Shandong Univ, Sch Pharmaceut Sci, Jinan, Peoples R China
10.Shandong Univ, Key Lab Infect & Immun Shandong Prov, Dept Pharmacol, Sch Basic Med Sci, Jinan, Peoples R China
推荐引用方式
GB/T 7714		 Yang, Fan,Mao, Chunyou,Guo, Lulu,et al. Structural basis of GPBAR activation and bile acid recognition[J]. NATURE,2020:29.
APA Yang, Fan.,Mao, Chunyou.,Guo, Lulu.,Lin, Jingyu.,Ming, Qianqian.,...&Zhang, Yan.(2020).Structural basis of GPBAR activation and bile acid recognition.NATURE,29.
MLA Yang, Fan,et al."Structural basis of GPBAR activation and bile acid recognition".NATURE (2020):29.

入库方式： OAI收割

来源：上海药物研究所

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