9P8X

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

Summary for 9P8X

• Entry DOI: 10.2210/pdb9p8x/pdb
• Descriptor: Ab#1-Fab Heavy Chain, Ab#1-Fab Light Chain, Tumor necrosis factor receptor superfamily member 18, ... (6 entities in total)
• Functional Keywords: gitr, gitrl, glucocorticoid-induced tnf receptor, tnfrsf18, tnfr, tnf, tumor necrosis factor receptor, antibody, fab, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 3
• Total formula weight: 61322.50

Authors

Huang, C.-S.,Mosyak, L.,Maben, Z. (deposition date: 2025-06-23, release date: 2025-12-31, Last modification date: 2026-01-28)

Primary citation

Yan, J.,Min-DeBartolo, J.,Huang, C.S.,Sharif, M.N.,Li, L.,Fish, S.,Dower, C.,Murphy, D.,Andreyeva, T.,Liu, H.,Han, X.,Zheng, W.,Ooi, J.H.,Edmonds, J.,Chen, T.,Maben, Z.,Stevens, C.R.,Goihberg, P.,Nocula-Lugowska, M.,Evans, S.M.,Mosyak, L.,Kelleher, K.,Dickinson, C.,Hegen, M.,Winkler, A.,Karlsson, F.
Ligand non-competitive GITR antibody prevents formation of the obligatory signal-triggering GITRL: GITR stoichiometry.
Sci Rep, 16:2752-2752, 2025

PubMed Abstract: 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.

PubMed: 41413164
DOI: 10.1038/s41598-025-32541-6

Experimental method

X-RAY DIFFRACTION (2.86 Å)