Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators

作     者：Song, Gaojie Yang, Dehua Wang, Yuxia de Graaf, Chris Zhou, Qingtong Jiang, Shanshan Liu, Kaiwen Cai, Xiaoqing Dai, Antao Lin, Guangyao Liu, Dongsheng Wu, Fan Wu, Yiran Zhao, Suwen Ye, Li Han, Gye Won Lau, Jesper Wu, Beili Hanson, Michael A. Liu, Zhi-Jie Wang, Ming-Wei Stevens, Raymond C. 

作者机构：ShanghaiTech Univ iHuman Inst 393 Middle Huaxia Rd Shanghai 201210 Peoples R China Chinese Acad Sci Shanghai Inst Mat Med Natl Ctr Drug Screening 189 Guo Shou Jing Rd Shanghai 201203 Peoples R China Chinese Acad Sci Shanghai Inst Mat Med CAS Key Lab Receptor Res 189 Guo Shou Jing Rd Shanghai 201203 Peoples R China Vrije Univ Amsterdam Fac Sci Div Med Chem AIMMS De Boelelaan 1108 NL-1081 HZ Amsterdam Netherlands Fudan Univ Sch Pharm 826 Zhang Heng Rd Shanghai 201203 Peoples R China ShanghaiTech Univ Sch Life Sci & Technol 393 Middle Huaxia Rd Shanghai 201210 Peoples R China Univ Chinese Acad Sci 19A Yuquan Rd Beijing 100049 Peoples R China Univ Southern Calif Bridge Inst Dept Chem 3430 S Vermont Ave Los Angeles CA 90089 USA Novo Nordisk DK-2760 Malov Denmark Chinese Acad Sci Shanghai Inst Mat Med CAS Key Lab Receptor Res 555 Zuchongzhi Rd Shanghai 201203 Peoples R China GPCR Consortium San Marcos CA 92078 USA Kunming Med Univ Inst Mol & Clin Med Kunming 650500 Peoples R China 

出 版 物：《NATURE》 (自然)

年 卷 期：2017年第546卷第7657期

页      面：312-+页

核心收录：

学科分类：07[理学] 08[工学] 

基　　金：National Natural Science Foundation of China [31330019, 31500593, 81373463, 81573479] National Health and Family Planning Commission [2012ZX09304-011, 2013ZX09401003-005, 2013ZX09507001, 2013ZX09507-002] Shanghai Science and Technology Development Fund [15DZ2291600] Ministry of Science and Technology of China [2014CB910400, 2015CB910104] Netherlands eScience Center (NLeSC)/NWO Enabling Technologies project: 3D-e-Chem [027.014.201] European Cooperation in Science and Technology Action GLISTEN [CM1207] National Key Research and Development Program of China [2016YCF0905902] Cloning, Cell Expression and Protein Purification Core Facilities of iHuman Institute Shanghai Municipal Government ShanghaiTech University GPCR Consortium 

主　　题：Nanocrystallography Drug discovery 

摘      要：The glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR) are members of the secretin-like class B family of G-protein-coupled receptors (GPCRs) and have opposing physiological roles in insulin release and glucose homeostasis(1). The treatment of type 2 diabetes requires positive modulation of GLP-1R to inhibit glucagon secretion and stimulate insulin secretion in a glucose-dependent manner(2). Here we report crystal structures of the human GLP-1R transmembrane domain in complex with two different negative allosteric modulators, PF-06372222 and NNC0640, at 2.7 and 3.0 angstrom resolution, respectively. The structures reveal a common binding pocket for negative allosteric modulators, present in both GLP-1R and GCGR(3) and located outside helices V-VII near the intracellular half of the receptor. The receptor is in an inactive conformation with compounds that restrict movement of the intracellular tip of helix VI, a movement that is generally associated with activation mechanisms in class A GPCRs(4-6). Molecular modelling and mutagenesis studies indicate that agonist positive allosteric modulators target the same general region, but in a distinct sub-pocket at the interface between helices V and VI, which may facilitate the formation of an intracellular binding site that enhances G-protein coupling.