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Nature. 2017 Jun 8;546(7657):312-315. doi: 10.1038/nature22378. Epub 2017 May 17.

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

Song G1, Yang D2, Wang Y1, de Graaf C3, Zhou Q1, Jiang S4, Liu K1,5,6, Cai X2, Dai A2, Lin G5, Liu D1, Wu F1,5,6, Wu Y1, Zhao S1,5, Ye L4, Han GW7, Lau J8, Wu B5,6,9, Hanson MA10, Liu ZJ1,5,11, Wang MW2,4,5, Stevens RC1,5.

Author information

1
iHuman Institute, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201210, China.
2
The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Shanghai 201203, China.
3
Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.
4
School of Pharmacy, Fudan University, 826 Zhang Heng Road, Shanghai 201203, China.
5
School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201210, China.
6
University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
7
Department of Chemistry, Bridge Institute, University of Southern California, 3430 S. Vermont Avenue, Los Angeles, California 90089, USA.
8
Novo Nordisk, Måløv DK-2760, Denmark.
9
The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
10
GPCR Consortium, San Marcos, California 92078, USA.
11
Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming 650500, China.

Abstract

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. 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. 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 Å resolution, respectively. The structures reveal a common binding pocket for negative allosteric modulators, present in both GLP-1R and GCGR 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. 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.

PMID:
28514449
DOI:
10.1038/nature22378
[Indexed for MEDLINE]

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