4LF3

Inhibitory Mechanism of an Allosteric Antibody Targeting the Glucagon Receptor

Summary for 4LF3

• Entry DOI: 10.2210/pdb4lf3/pdb
• Related: 4ERS 4LEX
• Descriptor: Fab heavy chain, Fab light chain, Glucagon receptor, ... (4 entities in total)
• Functional Keywords: fab fragment, gcgr, immune system
• Biological source: Mus musculus (mouse); More
• Cellular location: Cell membrane; Multi-pass membrane protein: P47871
• Total number of polymer chains: 6
• Total formula weight: 119231.48

Authors

Murray, J.M.,Mukund, S. (deposition date: 2013-06-26, release date: 2013-11-13, Last modification date: 2024-11-06)

Primary citation

Mukund, S.,Shang, Y.,Clarke, H.J.,Madjidi, A.,Corn, J.E.,Kates, L.,Kolumam, G.,Chiang, V.,Luis, E.,Murray, J.,Zhang, Y.,Hotzel, I.,Koth, C.M.,Allan, B.B.
Inhibitory mechanism of an allosteric antibody targeting the glucagon receptor.
J.Biol.Chem., 288:36168-36178, 2013

PubMed Abstract: Elevated glucagon levels and increased hepatic glucagon receptor (GCGR) signaling contribute to hyperglycemia in type 2 diabetes. We have identified a monoclonal antibody that inhibits GCGR, a class B G-protein coupled receptor (GPCR), through a unique allosteric mechanism. Receptor inhibition is mediated by the binding of this antibody to two distinct sites that lie outside of the glucagon binding cleft. One site consists of a patch of residues that are surface-exposed on the face of the extracellular domain (ECD) opposite the ligand-binding cleft, whereas the second binding site consists of residues in the αA helix of the ECD. A docking model suggests that the antibody does not occlude the ligand-binding cleft. We solved the crystal structure of GCGR ECD containing a naturally occurring G40S mutation and found a shift in the register of the αA helix that prevents antibody binding. We also found that alterations in the αA helix impact the normal function of GCGR. We present a model for the allosteric inhibition of GCGR by a monoclonal antibody that may form the basis for the development of allosteric modulators for the treatment of diabetes and other class B GPCR-related diseases.

PubMed: 24189067
DOI: 10.1074/jbc.M113.496984

Experimental method

X-RAY DIFFRACTION (2.735 Å)