Structure and Functional Binding Epitope of V-domain Ig Suppressor of T Cell Activation.

Cell reports (2019-09-05)
Nishant Mehta, Sainiteesh Maddineni, Irimpan I Mathews, R Andres Parra Sperberg, Po-Ssu Huang, Jennifer R Cochran

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 Å 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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Sodium chloride, for molecular biology, DNase, RNase, and protease, none detected, ≥99% (titration)
Trizma® hydrochloride solution, pH 8.0, BioPerformance Certified, 1 M, suitable for cell culture
HEPES sodium salt, ≥99.5% (titration)
Sodium bromide, ≥99.99% trace metals basis
Kifunensine, mannosidase inhibitor
HEPES sodium salt, ≥99.5% (titration), free-flowing, Redi-Dri

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