PDBsum entry 5e94

Membrane protein

PDB id: 5e94

Contents

Protein chains

214 a.a.

224 a.a.

110 a.a.

100 a.a.

Waters ×467

PDB id:

5e94

Name:

Membrane protein

Title:

Antibody-bound glucagon-like peptide-1 receptor extracellular domain

Structure:

Antibody fab fragment light chain. Chain: a, c. Engineered: yes. Antibody fab fragment heavy chain. Chain: b, d. Engineered: yes. Glucagon-like peptide 1 receptor. Chain: g, h. Fragment: n-terminal extracellular domain, unp residues 24-145.

Source:

Mus musculus. House mouse. Organism_taxid: 10090. Expressed in: homo sapiens. Expression_system_taxid: 9606. Homo sapiens. Human. Organism_taxid: 9606. Gene: glp1r.

Resolution:

2.00Å R-factor: 0.190 R-free: 0.232

Authors:

V.Soroka,G.Schluckebier,S.Reedtz-Runge

Key ref:

S.Hennen et al. (2016). Structural insight into antibody-mediated antagonism of the Glucagon-like peptide-1 Receptor. Sci Rep, 6, 26236. PubMed id: 27196125 DOI: 10.1038/srep26236

Date:

14-Oct-15 Release date: 24-Aug-16

Protein chains

No UniProt id for this chain

Struc: 214 a.a.

Protein chains

No UniProt id for this chain

Struc: 224 a.a.

Protein chain

P43220  (GLP1R_HUMAN) -  Glucagon-like peptide 1 receptor from Homo sapiens

Seq: 463 a.a.

Struc: 110 a.a.

Protein chain

P43220  (GLP1R_HUMAN) -  Glucagon-like peptide 1 receptor from Homo sapiens

Seq: 463 a.a.

Struc: 100 a.a.

DOI no: 10.1038/srep26236

Sci Rep 6:26236 (2016)

PubMed id: 27196125

Structural insight into antibody-mediated antagonism of the Glucagon-like peptide-1 Receptor.

S.Hennen, J.T.Kodra, V.Soroka, B.O.Krogh, X.Wu, P.Kaastrup, C.Ørskov, S.G.Rønn, G.Schluckebier, S.Barbateskovic, P.S.Gandhi, S.Reedtz-Runge.

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.