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

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

Author information

1
Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
2
Stanford Synchrotron Radiation Laboratory, 2575 Sand Hill Road, Menlo Park, CA 94025, USA.
3
Department of Bioengineering, Stanford University, Stanford, CA 94305, USA. Electronic address: possu@stanford.edu.
4
Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA. Electronic address: cochran1@stanford.edu.

Abstract

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

PMID:
31484064
DOI:
10.1016/j.celrep.2019.07.073
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