Structural basis of GPBAR activation and bile acid recognition

doi:10.1038/s41586-020-2569-1

	Structural basis of GPBAR activation and bile acid recognition
	Yang, Fan 8,12; Mao, Chunyou 9,10,11; Guo, Lulu 8,12; Lin, Jingyu 8,12; Ming, Qianqian 4,9,10,11; Xiao, Peng 8; Wu, Xiang 8; Shen, Qingya 9,10,11; Guo, Shimeng 13; Shen, Dan-Dan 9,10,11
刊名	NATURE
	2020-07-22
页码	29
ISSN号	0028-0836
DOI	10.1038/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.
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关键词	CRYO-EM STRUCTURE ; RECEPTOR ; MUTANT ; TGR5 ; VISUALIZATION ; VALIDATION ; INSIGHTS ; TOOLS ; MAPS
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	NATURE RESEARCH
WOS记录号	WOS:000580948000001
内容类型	期刊论文
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.Peking Univ, Key Lab Mol Cardiovasc Sci, Minist Educ, Dept Physiol & Pathophysiol,Sch Basic Med Sci, Beijing, Peoples R China 2.Shandong Univ, Sch Pharmaceut Sci, Jinan, Peoples R China 3.Shandong Univ, Key Lab Infect & Immun Shandong Prov, Dept Pharmacol, Sch Basic Med Sci, Jinan, Peoples R China 4.H Lee Moffitt Canc Ctr & Res Inst, Dept Drug Discovery, Tampa, FL USA 5.Univ Chinese Acad Sci, Sch Pharmaceut Sci & Technol, Hangzhou Inst Adv Study, Hangzhou, Peoples R China 6.Zhejiang Univ, Sch Med, Prot Facil, Hangzhou, Peoples R China 7.Zhejiang Univ, Sch Med, MOE Frontier Sci Ctr Brain Res & Brain Machine In, Hangzhou, Peoples R China 8.Shandong Univ, Key Lab Expt Teratol, Minist Educ, Dept Biochem & Mol Biol,Sch Basic Med Sci,Cheeloo, Jinan, Peoples R China 9.Zhejiang Univ, Sch Med, Dept Pathol, Sir Run Run Shaw Hosp, Hangzhou, Peoples R China 10.Zhejiang Univ, Sch Med, Dept Biophys, Hangzhou, 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.