Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex
文献类型：期刊论文
| 作者 | Liang, Yi-Lynn6,9; Khoshouei, Maryam7; Glukhova, Alisa6,9; Furness, Sebastian G. B.6,9; Zhao, Peishen6,9; Clydesdale, Lachlan6,9; Koole, Cassandra6,9; Truong, Tin T.6,9; Thal, David M.6,9; Lei, Saifei3,4,8 |
| 刊名 | NATURE
 |
| 出版日期 | 2018-03-01 |
| 卷号 | 555期号:7694页码:121-+ |
| ISSN号 | 0028-0836 |
| DOI | 10.1038/nature25773 |
| 文献子类 | Article |
| 英文摘要 | The class B glucagon-like peptide-1 (GLP-1) G protein-coupled receptor is a major target for the treatment of type 2 diabetes and obesity(1). Endogenous and mimetic GLP-1 peptides exhibit biased agonism-a difference in functional selectivity-that may provide improved therapeutic outcomes1. Here we describe the structure of the human GLP-1 receptor in complex with the G protein-biased peptide exendin-P5 and a G alpha(s) heterotrimer, determined at a global resolution of 3.3 angstrom. At the extracellular surface, the organization of extracellular loop 3 and proximal transmembrane segments differs between our exendin-P5-bound structure and previous GLP-1-bound GLP-1 receptor structure(2). At the intracellular face, there was a six-degree difference in the angle of the G alpha(s)-alpha 5 helix engagement between structures, which was propagated across the G protein heterotrimer. In addition, the structures differed in the rate and extent of conformational reorganization of the G alpha(s) protein. Our structure provides insights into the molecular basis of biased agonism. |
| WOS关键词 | GLUCAGON-LIKE PEPTIDE-1 ; PROTEIN-COUPLED RECEPTOR ; ELECTRON-MICROSCOPY ; CRYSTAL-STRUCTURE ; LIGAND-BINDING ; ACTIVATION ; DOMAIN ; RESIDUES ; MUTANT ; MODULATION |
| 资助项目 | Monash University Ramaciotti Centre for Cryo-Electron Microscopy[00000000] ; National Health and Medical Research Council of Australia (NHMRC)[1061044] ; National Health and Medical Research Council of Australia (NHMRC)[1065410] ; National Health and Medical Research Council of Australia (NHMRC)[1120919] ; National Health and Medical Research Council of Australia (NHMRC)[1126857] ; NHMRC[1055134] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020347] ; Shanghai Science and Technology Development Fund[15DZ2291600] ; CAS[00000000] |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| WOS记录号 | WOS:000426247600044 |
| 出版者 | NATURE PUBLISHING GROUP |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279878]  |
| 专题 | 国家新药筛选中心 |
| 通讯作者 | Sexton, Patrick M.; Wootten, Denise |
| 作者单位 | 1.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China; 2.FEI, NL-5651 GG Eindhoven, Netherlands; 3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 5.Mayo Clin, Dept Mol Pharmacol & Expt Therapeut, Scottsdale, AZ 85259 USA 6.Monash Univ, Monash Inst Pharmaceut Sci, Dept Pharmacol, Parkville, Vic 3052, Australia; 7.Max Planck Inst Biochem, Dept Mol Struct Biol, D-82152 Martinsried, Germany; 8.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China; 9.Monash Univ, Monash Inst Pharmaceut Sci, Drug Discovery Biol, Parkville, Vic 3052, Australia; |
| 推荐引用方式 GB/T 7714 | Liang, Yi-Lynn,Khoshouei, Maryam,Glukhova, Alisa,et al. Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex[J]. NATURE,2018,555(7694):121-+. |
| APA | Liang, Yi-Lynn.,Khoshouei, Maryam.,Glukhova, Alisa.,Furness, Sebastian G. B..,Zhao, Peishen.,...&Wootten, Denise.(2018).Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex.NATURE,555(7694),121-+. |
| MLA | Liang, Yi-Lynn,et al."Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex".NATURE 555.7694(2018):121-+. |
入库方式： OAI收割
来源：上海药物研究所
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