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Inhibitory Mechanism of an Allosteric Antibody Targeting the Glucagon Receptor
Authors:Susmith Mukund  Yonglei Shang  Holly J Clarke  Azadeh Madjidi  Jacob E Corn  Lance Kates  Ganesh Kolumam  Vicky Chiang  Elizabeth Luis  Jeremy Murray  Yingnan Zhang  Isidro H?tzel  Christopher M Koth  Bernard B Allan
Institution:From the Departments of Structural Biology.;§Antibody Engineering.;Molecular Biology.;**Biomedical Imaging.;‡‡Protein Chemistry, and ;Early Discovery Biochemistry, Genentech, Inc., South San Francisco, California 94080
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.
Keywords:Antibody Engineering  Diabetes  G Protein-coupled Receptors (GPCR)  Glucose Metabolism  Structural Biology
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