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Publication Abstract from PubMed

The Glucagon-like peptide-1 receptor (GLP-1R) is a member of the class B G protein-coupled receptor (GPCR) family and a well-established target for the treatment of type 2 diabetes. The N-terminal extracellular domain (ECD) of GLP-1R is important for GLP-1 binding and the crystal structure of the GLP-1/ECD complex was reported previously. The first structure of a class B GPCR transmembrane (TM) domain was solved recently, but the full length receptor structure is still not well understood. Here we describe the molecular details of antibody-mediated antagonism of the GLP-1R using both in vitro pharmacology and x-ray crystallography. We showed that the antibody Fab fragment (Fab 3F52) blocked the GLP-1 binding site of the ECD directly and thereby acts as a competitive antagonist of native GLP-1. Interestingly, Fab 3F52 also blocked a short peptide agonist believed to engage primarily the transmembrane and extracellular loop region of GLP-1R, whereas functionality of an allosteric small-molecule agonist was not inhibited. This study has implications for the structural understanding of the GLP-1R and related class B GPCRs, which is important for the development of new and improved therapeutics targeting these receptors.

Structural insight into antibody-mediated antagonism of the Glucagon-like peptide-1 Receptor.,Hennen S, Kodra JT, Soroka V, Krogh BO, Wu X, Kaastrup P, Orskov C, Ronn SG, Schluckebier G, Barbateskovic S, Gandhi PS, Reedtz-Runge S Sci Rep. 2016 May 19;6:26236. doi: 10.1038/srep26236. PMID:27196125^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.