7RFP

Mouse GITR (mGITR) with DTA-1 Fab fragment

Summary for 7RFP

• Entry DOI: 10.2210/pdb7rfp/pdb
• EMDB information: 24444
• Descriptor: Tumor necrosis factor receptor superfamily member 18,Enhanced green fluorescent protein, DTA-1 (heavy chain), DTA-1 (light chain) (3 entities in total)
• Functional Keywords: mouse glucocorticoid-induced tumor necrosis factor receptor, mgitr, tnf receptor, dta-1, immune system
• Biological source: Mus musculus (Mouse); More
• Total number of polymer chains: 6
• Total formula weight: 264365.83

Authors

Meyerson, J.R.,He, C. (deposition date: 2021-07-14, release date: 2022-03-09)

Primary citation

He, C.,Maniyar, R.R.,Avraham, Y.,Zappasodi, R.,Rusinova, R.,Newman, W.,Heath, H.,Wolchok, J.D.,Dahan, R.,Merghoub, T.,Meyerson, J.R.
Therapeutic antibody activation of the glucocorticoid-induced TNF receptor by a clustering mechanism.
Sci Adv, 8:eabm4552-eabm4552, 2022

PubMed Abstract: GITR 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.

PubMed: 35213218
DOI: 10.1126/sciadv.abm4552

Experimental method

ELECTRON MICROSCOPY (4.4 Å)