PT  - JOURNAL ARTICLE
AU  - Nishant Mehta
AU  - Sainiteesh Maddineni
AU  - Irimpan I. Mathews
AU  - Andres Parra Sperberg
AU  - Po-Ssu Huang
AU  - Jennifer R. Cochran
TI  - Structure and Functional Binding Epitope of V-domain Ig Suppressor of T-cell Activation (VISTA)
AID  - 10.1101/597716
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 597716
4099  - http://biorxiv.org/content/early/2019/04/03/597716.short
4100  - http://biorxiv.org/content/early/2019/04/03/597716.full
AB  - 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 Å 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.