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

Cell Rep. 2019 Sep 3;28(10):2509-2516.e5. doi: 10.1016/j.celrep.2019.07.073.


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.

Keywords: B7-H5; IGSF11; PD-1H; VISTA; VSIG3; cancer immunotherapy; checkpoint inhibitor; epitope mapping; high resolution crystal structure; yeast display.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • B7 Antigens / chemistry*
  • B7 Antigens / metabolism*
  • Crystallization
  • Epitope Mapping
  • Epitopes / metabolism*
  • Humans
  • Protein Binding
  • Protein Domains


  • B7 Antigens
  • Epitopes
  • VSIR protein, human