5E94

Antibody-bound Glucagon-like Peptide-1 receptor extracellular domain

Summary for 5E94

• Entry DOI: 10.2210/pdb5e94/pdb
• Descriptor: Antibody Fab fragment light chain, Antibody Fab fragment heavy chain, Glucagon-like peptide 1 receptor, ... (4 entities in total)
• Functional Keywords: antibody antagonist glp-1 receptor, immune system, membrane protein
• Biological source: Mus musculus (House Mouse); More
• Cellular location: Cell membrane ; Multi- pass membrane protein : P43220
• Total number of polymer chains: 6
• Total formula weight: 125380.77

Authors

Soroka, V.,Schluckebier, G.,Reedtz-Runge, S. (deposition date: 2015-10-14, release date: 2016-08-24, Last modification date: 2024-11-06)

Primary citation

Hennen, S.,Kodra, J.T.,Soroka, V.,Krogh, B.O.,Wu, X.,Kaastrup, P.,Orskov, C.,Ronn, S.G.,Schluckebier, G.,Barbateskovic, S.,Gandhi, P.S.,Reedtz-Runge, S.
Structural insight into antibody-mediated antagonism of the Glucagon-like peptide-1 Receptor.
Sci Rep, 6:26236-26236, 2016

PubMed Abstract: 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.

PubMed: 27196125
DOI: 10.1038/srep26236

Experimental method

X-RAY DIFFRACTION (2 Å)