Journal
PHARMACOLOGICAL REVIEWS
Volume 68, Issue 4, Pages 954-1013Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/pr.115.011395
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Funding
- National Health and Family Planning Commission of China [2012ZX09304-011, 2013ZX09401003-005, 2013ZX09507001, 2013ZX09507-002]
- Chinese Academy of Sciences
- Shanghai Science and Technology Development Fund [15DZ2291600]
- Thousand Talents Program in China
- National Natural Science Foundation of China [81373463]
- National Health and Medical Research Council of Australia (NHMRC) Principal Research Fellowship
- NHMRC [1055134, 1061044, 1065410]
- CAS-Novo Nordisk Research Fund
- Welch Foundation [AT-1595]
- Juvenile Diabetes Research Foundation [37-2011-20]
- National Health and Medical Research Council of Australia [1061044, 1065410] Funding Source: NHMRC
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The glucagon-like peptide (GLP)-1 receptor (GLP-1R) is a class B G protein-coupled receptor (GPCR) that mediates the action of GLP-1, a peptide hormone secreted from three major tissues in humans, enteroendocrine L cells in the distal intestine, a cells in the pancreas, and the central nervous system, which exerts important actions useful in the management of type 2 diabetes mellitus and obesity, including glucose homeostasis and regulation of gastric motility and food intake. Peptidic analogs of GLP-1 have been successfully developed with enhanced bioavailability and pharmacological activity. Physiologic and biochemical studies with truncated, chimeric, and mutated peptides and GLP-1R variants, together with ligand-bound crystal structures of the extracellular domain and the first three-dimensional structures of the 7-helical transmembrane domain of class B GPCRs, have provided the basis for a two-domain-binding mechanism of GLP-1 with its cognate receptor. Although efforts in discovering therapeutically viable nonpeptidic GLP-1R agonists have been hampered, small-molecule modulators offer complementary chemical tools to peptide analogs to investigate ligand-directed biased cellular signaling of GLP-1R. The integrated pharmacological and structural information of different GLP-1 analogs and homologous receptors give new insights into the molecular determinants of GLP-1R ligand selectivity and functional activity, thereby providing novel opportunities in the design and development of more efficacious agents to treat metabolic disorders.
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