PT  - JOURNAL ARTICLE
AU  - Graaf, Chris de
AU  - Donnelly, Dan
AU  - Wootten, Denise
AU  - Lau, Jesper
AU  - Sexton, Patrick M.
AU  - Miller, Laurence J.
AU  - Ahn, Jung-Mo
AU  - Liao, Jiayu
AU  - Fletcher, Madeleine M.
AU  - Yang, Dehua
AU  - Brown, Alastair J. H.
AU  - Zhou, Caihong
AU  - Deng, Jiejie
AU  - Wang, Ming-Wei
ED  - DEQUAN YE, RICHARD
TI  - Glucagon-Like Peptide-1 and Its Class B G Protein–Coupled Receptors: A Long March to Therapeutic Successes
AID  - 10.1124/pr.115.011395
DP  - 2016 Oct 01
TA  - Pharmacological Reviews
PG  - 954--1013
VI  - 68
IP  - 4
4099  - http://pharmrev.aspetjournals.org/content/68/4/954.short
4100  - http://pharmrev.aspetjournals.org/content/68/4/954.full
SO  - Pharmacol Rev2016 Oct 01; 68
AB  - 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, α 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.