9p8x

Crystal structure of GITR in complex with ligand-non-competitive Ab#1 Fab fragment

spinqualitylabelsall models 9p8x, resolution 2.86Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9p8x is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.86Å Ligands: ACT, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function TNR18_HUMAN Receptor for TNFSF18. Seems to be involved in interactions between activated T-lymphocytes and endothelial cells and in the regulation of T-cell receptor-mediated cell death. Mediated NF-kappa-B activation via the TRAF2/NIK pathway. Publication Abstract from PubMed The prevalence of autoimmune diseases such as inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) is increasing. Glucocorticoid-induced TNFR-related protein (GITR), a TNF receptor superfamily (TNFRSF) member, is activated by GITR-ligand (GITRL). GITR signaling is pathogenic in models of RA and IBD, leading to lymphocyte proliferation and secretion of pro-inflammatory cytokines. Despite promising preclinical data, GITR neutralization in autoimmune diseases remains under-explored, due to challenges in avoiding antibody-mediated GITR activation. Therefore, we developed a human GITR-specific antibody that inhibits GITRL-mediated GITR-signaling, while preserving the GITRL epitope on GITR. The antibody strongly inhibited GITR signaling in the in vitro assays via a novel mechanism of disrupting downstream higher-order structures rather than direct blocking of GITR binding. Even though the antibody did not demonstrate efficacy in an NSG human skin graft transplant model, this general mechanism might be a viable therapeutic intervention for other TNFRSF members relying more significantly on soluble ligands. Ligand non-competitive GITR antibody prevents formation of the obligatory signal-triggering GITRL: GITR stoichiometry.,Yan J, Min-DeBartolo J, Huang CS, Sharif MN, Li L, Fish S, Dower C, Murphy D, Andreyeva T, Liu H, Han X, Zheng W, Ooi JH, Edmonds J, Chen T, Maben Z, Stevens CR, Goihberg P, Nocula-Lugowska M, Evans SM, Mosyak L, Kelleher K, Dickinson C, Hegen M, Winkler A, Karlsson F Sci Rep. 2025 Dec 18. doi: 10.1038/s41598-025-32541-6. PMID:41413164 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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