TY - JOUR
T1 - Glucagon-like peptide-1 and its class B G protein-coupled receptors
T2 - a long march to therapeutic successes
AU - de Graaf, Chris
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
PY - 2016/10/1
Y1 - 2016/10/1
N2 - The glucagon-likepeptide (GLP)-1receptor (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 non peptidic 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.
AB - The glucagon-likepeptide (GLP)-1receptor (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 non peptidic 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.
UR - http://www.scopus.com/inward/record.url?scp=84988028207&partnerID=8YFLogxK
U2 - 10.1124/pr.115.011395
DO - 10.1124/pr.115.011395
M3 - Review Article
AN - SCOPUS:84988028207
SN - 1521-0081
VL - 68
SP - 954
EP - 1013
JO - Pharmacological Reviews
JF - Pharmacological Reviews
IS - 4
ER -
