6O9I

Ternary complex of mouse ECD with Fab1 and Fab2

Summary for 6O9I

• Entry DOI: 10.2210/pdb6o9i/pdb
• Descriptor: Fab1 heavy chain, Fab1 light chain, Gastric inhibitory polypeptide receptor, ... (7 entities in total)
• Functional Keywords: gpcr, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 5
• Total formula weight: 112930.78

Authors

Min, X.,Wang, Z. (deposition date: 2019-03-13, release date: 2020-01-22, Last modification date: 2024-11-20)

Primary citation

Min, X.,Yie, J.,Wang, J.,Chung, B.C.,Huang, C.S.,Xu, H.,Yang, J.,Deng, L.,Lin, J.,Chen, Q.,Abbott, C.M.,Gundel, C.,Thibault, S.A.,Meng, T.,Bates, D.L.,Lloyd, D.J.,Veniant, M.M.,Wang, Z.
Molecular mechanism of an antagonistic antibody against glucose-dependent insulinotropic polypeptide receptor.
Mabs, 12:1710047-1710047, 2020

PubMed Abstract: Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone involved in regulating glucose and lipid metabolism. GIP receptor (GIPR) antagonism is believed to offer therapeutic potential for various metabolic diseases. Pharmacological intervention of GIPR, however, has limited success due to lack of effective antagonistic reagents. Previously we reported the discovery of two mouse anti-murine GIPR monoclonal antibodies (mAbs) with distinctive properties in rodent models. Here, we report the detailed structural and biochemical characterization of these two antibodies, mAb1 and mAb2. and characterizations demonstrated mAb2 is a full GIPR antagonistic antibody and mAb1 is a non-neutralizing GIPR binder. To understand the molecular basis of these two antibodies, we determined the co-crystal structures of GIPR extracellular domain in complex with mAb1 and with mAb2 at resolutions of 2.1 and 2.6 Å, respectively. While the non-neutralizing mAb1 binds to GIPR without competing with the ligand peptide, mAb2 not only partially occludes the ligand peptide binding, but also recognizes the GIPR C-terminal stalk region in a helical conformation that acts as a molecular mimic of the ligand peptide and locks GIPR in a novel auto-inhibited state. Furthermore, administration of mAb2 in diet-induced obesity mice for 7 weeks leads to both reduction in body weight gain and improvement of metabolic profiles. In contrast, mAb1 has no effect on body weight or other metabolic improvement. Together, our studies reveal the unique molecular mechanism of action underlying the superior antagonistic activity of mAb2 and signify the promising therapeutic potential of effective GIPR antagonism for the treatment of metabolic disorders.

PubMed: 31905038
DOI: 10.1080/19420862.2019.1710047

Experimental method

X-RAY DIFFRACTION (2.6 Å)