Glucagon-like peptide-1 and its class B G protein-coupled receptors: A long march to therapeutic successes

Chris de Graaf, Dan Donnelly, Denise Wootten, Jesper Lau, Patrick M. Sexton, Laurence J. Miller, Jung Mo Ahn, Jiayu Liao, Madeleine M. Fletcher, Dehua Yang, Alastair J.H. Brown, Caihong Zhou, Jiejie Deng, Ming Wei Wang

Research output: Contribution to journalArticlepeer-review

124 Scopus citations


Theglucagon-likepeptide (GLP)-1receptor (GLP-1R) is a class B G protein-coupled receptor (GPCR) that mediates the action of GLP-1, a peptide hormone secretedfromthreemajor tissues inhumans,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 twodomain-binding mechanism of GLP-1 with its cognate receptor. Although efforts in discovering therapeutically viable nonpeptidicGLP-1R agonists have been hampered, small-moleculemodulators 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.

Original languageEnglish (US)
Pages (from-to)954-1013
Number of pages60
JournalPharmacological Reviews
Issue number4
StatePublished - Oct 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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