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bioRxiv · 10.1101/597716

Structure and Functional Binding Epitope of V-domain Ig Suppressor of T-cell Activation (VISTA)

Mehta, N.·Maddineni, S.·Mathews, I. I.·Sperberg, A. P.·Huang, P.-S.·Cochran, J. R.
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Abstract

V-domain 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, antibodies that block VISTA signaling can release the brakes of the immune system and promote tumor clearance. VISTA has an Ig-like fold, but little is known about its structure and mechanism of action. Here, we report a 1.85 [A] crystal structure of the human VISTA extracellular domain and highlight structural features that make VISTA unique among B7 family members. Through fine-epitope mapping, we also identify solvent-exposed residues that underlie binding to a clinically relevant anti-VISTA antibody. This antibody-binding region is also shown to interact with V-set and Ig domain-containing 3 (VSIG3), the recently proposed functional binding partner of VISTA. The structure and functional epitope determined here will help guide future drug development efforts against this important checkpoint target.

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Mehta, N., Maddineni, S., Mathews, I. I., Sperberg, A. P., Huang, P.-S., Cochran, J. R.. 2019-04-03. Structure and Functional Binding Epitope of V-domain Ig Suppressor of T-cell Activation (VISTA). https://doi.org/10.1101/597716

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