期刊
NATURE
卷 546, 期 7657, 页码 312-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature22378
关键词
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资金
- 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
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.
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