6DKJ
human GIPR ECD and Fab complex
Summary for 6DKJ
| Entry DOI | 10.2210/pdb6dkj/pdb |
| Descriptor | Fab heavy chain, Fab light chain, Gastric inhibitory polypeptide receptor, ... (5 entities in total) |
| Functional Keywords | gpcr, signaling protein |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 6 |
| Total formula weight | 121046.82 |
| Authors | |
| Primary citation | Killion, E.A.,Wang, J.,Yie, J.,Shi, S.D.,Bates, D.,Min, X.,Komorowski, R.,Hager, T.,Deng, L.,Atangan, L.,Lu, S.C.,Kurzeja, R.J.M.,Sivits, G.,Lin, J.,Chen, Q.,Wang, Z.,Thibault, S.A.,Abbott, C.M.,Meng, T.,Clavette, B.,Murawsky, C.M.,Foltz, I.N.,Rottman, J.B.,Hale, C.,Veniant, M.M.,Lloyd, D.J. Anti-obesity effects of GIPR antagonists alone and in combination with GLP-1R agonists in preclinical models. Sci Transl Med, 10:-, 2018 Cited by PubMed Abstract: Glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) has been identified in multiple genome-wide association studies (GWAS) as a contributor to obesity, and GIPR knockout mice are protected against diet-induced obesity (DIO). On the basis of this genetic evidence, we developed anti-GIPR antagonistic antibodies as a potential therapeutic strategy for the treatment of obesity and observed that a mouse anti-murine GIPR antibody (muGIPR-Ab) protected against body weight gain, improved multiple metabolic parameters, and was associated with reduced food intake and resting respiratory exchange ratio (RER) in DIO mice. We replicated these results in obese nonhuman primates (NHPs) using an anti-human GIPR antibody (hGIPR-Ab) and found that weight loss was more pronounced than in mice. In addition, we observed enhanced weight loss in DIO mice and NHPs when anti-GIPR antibodies were codosed with glucagon-like peptide-1 receptor (GLP-1R) agonists. Mechanistic and crystallographic studies demonstrated that hGIPR-Ab displaced GIP and bound to GIPR using the same conserved hydrophobic residues as GIP. Further, using a conditional knockout mouse model, we excluded the role of GIPR in pancreatic β-cells in the regulation of body weight and response to GIPR antagonism. In conclusion, these data provide preclinical validation of a therapeutic approach to treat obesity with anti-GIPR antibodies. PubMed: 30567927DOI: 10.1126/scitranslmed.aat3392 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.95 Å) |
Structure validation
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