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Activation of the GLP-1 receptor by a non-peptidic agonist

文献类型：期刊论文

作者Zhao, Peishen1; Liang, Yi-Lynn1; Belousoff, Matthew J.1; Deganutti, Giuseppe2; Fletcher, Madeleine M.1; Willard, Francis S.3; Bell, Michael G.3; Christe, Michael E.3; Sloop, Kyle W.3; Inoue, Asuka4
刊名NATURE
出版日期2020-01-08
页码432-+
ISSN号0028-0836
DOI10.1038/s41586-019-1902-z
通讯作者Danev, Radostin(rado@m.u-tokyo.ac.jp) ; Sexton, Patrick M.(patrick.sexton@monash.edu) ; Wootten, Denise(denise.wootten@monash.edu)
英文摘要Class B G-protein-coupled receptors are major targets for the treatment of chronic diseases, including diabetes and obesity(1). Structures of active receptors reveal peptide agonists engage deep within the receptor core, leading to an outward movement of extracellular loop 3 and the tops of transmembrane helices 6 and 7, an inward movement of transmembrane helix 1, reorganization of extracellular loop 2 and outward movement of the intracellular side of transmembrane helix 6, resulting in G-protein interaction and activation(2-6). Here we solved the structure of a non-peptide agonist, TT-OAD2, bound to the glucagon-like peptide-1 (GLP-1) receptor. Our structure identified an unpredicted non-peptide agonist-binding pocket in which reorganization of extracellular loop 3 and transmembrane helices 6 and 7 manifests independently of direct ligand interaction within the deep transmembrane domain pocket. TT-OAD2 exhibits biased agonism, and kinetics of G-protein activation and signalling that are distinct from peptide agonists. Within the structure, TT-OAD2 protrudes beyond the receptor core to interact with the lipid or detergent, providing an explanation for the distinct activation kinetics that may contribute to the clinical efficacy of this compound series. This work alters our understanding of the events that drive the activation of class B receptors.
WOS关键词CRYO-EM STRUCTURE ; GENERAL FORCE-FIELD ; G-PROTEIN ; PEPTIDE-1 RECEPTOR ; MOLECULAR-DYNAMICS ; CRYSTAL-STRUCTURE ; COMPLEX ; AUTOMATION ; MODULATION ; EFFICACY
WOS研究方向Science & Technology - Other Topics
语种英语
出版者NATURE PUBLISHING GROUP
WOS记录号WOS:000510801600002
源URL[http://119.78.100.183/handle/2S10ELR8/281605]  
专题中国科学院上海药物研究所
通讯作者Danev, Radostin; Sexton, Patrick M.; Wootten, Denise
作者单位1.Monash Univ, Monash Inst Pharmaceut Sci, Drug Discovery Biol, Parkville, Vic, Australia
2.Univ Essex, Sch Biol Sci, Colchester, Essex, England
3.Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA
4.Tohoku Univ, Grad Sch Pharmaceut Sci, Sendai, Miyagi, Japan
5.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, Shanghai, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China
7.Fudan Univ, Sch Pharm, Shanghai, Peoples R China
8.Mayo Clin, Scottsdale, AZ USA
9.Univ Tokyo, Grad Sch Med, Bunkyo Ku, Tokyo, Japan
推荐引用方式
GB/T 7714		 Zhao, Peishen,Liang, Yi-Lynn,Belousoff, Matthew J.,et al. Activation of the GLP-1 receptor by a non-peptidic agonist[J]. NATURE,2020:432-+.
APA Zhao, Peishen.,Liang, Yi-Lynn.,Belousoff, Matthew J..,Deganutti, Giuseppe.,Fletcher, Madeleine M..,...&Wootten, Denise.(2020).Activation of the GLP-1 receptor by a non-peptidic agonist.NATURE,432-+.
MLA Zhao, Peishen,et al."Activation of the GLP-1 receptor by a non-peptidic agonist".NATURE (2020):432-+.

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来源：上海药物研究所

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