7rfp | pdb_00007rfp
Mouse GITR (mGITR) with DTA-1 Fab fragment
Structural highlights
FunctionTNR18_MOUSE 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 (By similarity). Publication Abstract from PubMedGITR is a TNF receptor, and its activation promotes immune responses and drives antitumor activity. The receptor is activated by the GITR ligand (GITRL), which is believed to cluster receptors into a high-order array. Immunotherapeutic agonist antibodies also activate the receptor, but their mechanisms are not well characterized. We solved the structure of full-length mouse GITR bound to Fabs from the antibody DTA-1. The receptor is a dimer, and each subunit binds one Fab in an orientation suggesting that the antibody clusters receptors. Binding experiments with purified proteins show that DTA-1 IgG and GITRL both drive extensive clustering of GITR. Functional data reveal that DTA-1 and the anti-human GITR antibody TRX518 activate GITR in their IgG forms but not as Fabs. Thus, the divalent character of the IgG agonists confers an ability to mimic GITRL and cluster and activate GITR. These findings will inform the clinical development of this class of antibodies for immuno-oncology. Therapeutic antibody activation of the glucocorticoid-induced TNF receptor by a clustering mechanism.,He C, Maniyar RR, Avraham Y, Zappasodi R, Rusinova R, Newman W, Heath H, Wolchok JD, Dahan R, Merghoub T, Meyerson JR Sci Adv. 2022 Feb 25;8(8):eabm4552. doi: 10.1126/sciadv.abm4552. Epub 2022 Feb , 25. PMID:35213218[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also
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