Journal
CELL REPORTS
Volume 28, Issue 10, Pages 2509-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2019.07.073
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Funding
- U.S. Department of Energy, Office of Science [DE-AC02-76SF00515]
- DOE Office of Biological and Environmental Research
- NIH National Institute of General Medical Sciences [P41GM103393]
- Stanford Bio-X IIP Interdisciplinary Initiatives Seed Grants Program
- NSF Graduate Research Fellowship
- Stanford Graduate Fellowship
- Stanford Bio-X Undergraduate Summer Research Program
- Stanford NIST Predoctoral Training Grant Program
- U.S. Department of Energy, Office of Basic Energy Sciences [DE-AC02-76SF00515]
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V-domain immunoglobulin (Ig) suppressor of T cell activation (VISTA) is an immune checkpoint protein that inhibits the T cell response against cancer. Similar to PD-1 and CTLA-4, a blockade of VISTA promotes tumor clearance by the immune system. Here, we report a 1.85 angstrom crystal structure of the elusive human VISTA extracellular domain, whose lack of homology necessitated a combinatorial MR-Rosetta approach for structure determination. We highlight features that make the VISTA immunoglobulin variable (IgV)-like fold unique among B7 family members, including two additional disulfide bonds and an extended loop region with an attached helix that we show forms a contiguous binding epitope for a clinically relevant anti-VISTA antibody. We propose an overlap of this antibody-binding region with the binding epitope for V-set and Ig domain containing 3 (VSIG3), a purported functional binding partner of VISTA. The structure and functional epitope presented here will help guide future drug development efforts against this important checkpoint target.
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