6MVL
Crystal structure of VISTA bound to a pH-selective antibody Fab fragment
Summary for 6MVL
| Entry DOI | 10.2210/pdb6mvl/pdb |
| Descriptor | V-type immunoglobulin domain-containing suppressor of T-cell activation, Antibody Fab fragment heavy chain, Antibody Fab fragment light chain, ... (6 entities in total) |
| Functional Keywords | immunoglobulin, checkpoint, antibody, complex, immune system |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 3 |
| Total formula weight | 68404.41 |
| Authors | Critton, D.A. (deposition date: 2018-10-26, release date: 2019-10-23, Last modification date: 2024-10-23) |
| Primary citation | Johnston, R.J.,Su, L.J.,Pinckney, J.,Critton, D.,Boyer, E.,Krishnakumar, A.,Corbett, M.,Rankin, A.L.,Dibella, R.,Campbell, L.,Martin, G.H.,Lemar, H.,Cayton, T.,Huang, R.Y.,Deng, X.,Nayeem, A.,Chen, H.,Ergel, B.,Rizzo, J.M.,Yamniuk, A.P.,Dutta, S.,Ngo, J.,Shorts, A.O.,Ramakrishnan, R.,Kozhich, A.,Holloway, J.,Fang, H.,Wang, Y.K.,Yang, Z.,Thiam, K.,Rakestraw, G.,Rajpal, A.,Sheppard, P.,Quigley, M.,Bahjat, K.S.,Korman, A.J. VISTA is an acidic pH-selective ligand for PSGL-1. Nature, 574:565-570, 2019 Cited by PubMed Abstract: Co-inhibitory immune receptors can contribute to T cell dysfunction in patients with cancer. Blocking antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) partially reverse this effect and are becoming standard of care in an increasing number of malignancies. However, many of the other axes by which tumours become inhospitable to T cells are not fully understood. Here we report that V-domain immunoglobulin suppressor of T cell activation (VISTA) engages and suppresses T cells selectively at acidic pH such as that found in tumour microenvironments. Multiple histidine residues along the rim of the VISTA extracellular domain mediate binding to the adhesion and co-inhibitory receptor P-selectin glycoprotein ligand-1 (PSGL-1). Antibodies engineered to selectively bind and block this interaction in acidic environments were sufficient to reverse VISTA-mediated immune suppression in vivo. These findings identify a mechanism by which VISTA may engender resistance to anti-tumour immune responses, as well as an unexpectedly determinative role for pH in immune co-receptor engagement. PubMed: 31645726DOI: 10.1038/s41586-019-1674-5 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.61 Å) |
Structure validation
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