6o9i

Ternary complex of mouse ECD with Fab1 and Fab2

spinqualitylabelsall models 6o9i, resolution 2.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6o9i is a 5 chain structure with sequence from Human and Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: EDO NonStd Res: PCA Gene: Gipr (LK3 transgenic mice) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [GIPR_MOUSE] This is a receptor for GIP. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase (By similarity). Publication Abstract from PubMed 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. In vitro and in vivo 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 A, 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. Molecular mechanism of an antagonistic antibody against glucose-dependent insulinotropic polypeptide receptor.,Min X, Yie J, Wang J, Chung BC, Huang CS, Xu H, Yang J, Deng L, Lin J, Chen Q, Abbott CM, Gundel C, Thibault SA, Meng T, Bates DL, Lloyd DJ, Veniant MM, Wang Z MAbs. 2020 Jan-Dec;12(1):1710047. doi: 10.1080/19420862.2019.1710047. PMID:31905038 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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