期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 291, 期 25, 页码 12991-13004出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M116.721977
关键词
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资金
- Ministry of Science and Technology of China [2012CB518005, 2012AA020302, 2013ZX09507001, 91313000]
- National Natural Science Foundation of China [81573479, 81373463, 21422208, 81230076, 21210003]
- National Health and Family Planning Commission of China [2013ZX09507001, 2012ZX09304-011, 2013ZX09401003-005, 2013ZX09507-002]
- Shanghai Science and Technology Development Fund [15DZ2291600, 14431901200]
- National Institutes of Health [U54 GM094618]
- European Cooperation in Science and Technology Action [CM1207]
- Netherlands eScience Center (NLeSC)/Netherlands Organisation for Scientific Research (NWO) Enabling Technologies Project, 3D-e-Chem [027.014.201]
- CAS-Novo Nordisk Research Fund
- SA-SIBS Scholarship Program
- Thousand Talents Program in China (Chinese Academy of Sciences)
The glucagon-like peptide-1 receptor (GLP-1R) belongs to the secretin-like (class B) family of G protein-coupled receptors. Members of the class B family are distinguished by their large extracellular domain, which works cooperatively with the canonical seven-transmembrane (7TM) helical domain to signal in response to binding of various peptide hormones. We have combined structure-based site-specific mutational studies with molecular dynamics simulations of a full-length model of GLP-1R bound to multiple peptide ligand variants. Despite the high sequence similarity between GLP-1R and its closest structural homologue, the glucagon receptor (GCGR), nearly half of the 62 stably expressed mutants affected GLP-1R in a different manner than the corresponding mutants in GCGR. The molecular dynamics simulations of wild-type and mutant GLP-1R center dot ligand complexes provided molecular insights into GLP-1R-specific recognition mechanisms for the N terminus of GLP-1 by residues in the 7TM pocket and explained how glucagon-mimicking GLP-1 mutants restored binding affinity for (GCGR-mimicking) GLP-1R mutants. Structural analysis of the simulations suggested that peptide ligand binding mode variations in the 7TM binding pocket are facilitated by movement of the extracellular domain relative to the 7TM bundle. These differences in binding modes may account for the pharmacological differences between GLP-1 peptide variants.
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