Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
Stanford Synchrotron Radiation Laboratory, 2575 Sand Hill Road, Menlo Park, CA 94025, USA.
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.
V 结构域免疫球蛋白（Ig）抑制 T 细胞活化（VISTA）是一种免疫检查点蛋白，可抑制针对癌症的 T 细胞反应。与 PD-1 和 CTLA-4 类似，VISTA 的阻断可促进免疫系统清除肿瘤。在这里，我们报告了难以捉摸的人类 VISTA 细胞外结构域的 1.85Å 晶体结构，由于缺乏同源性，因此需要采用组合的 MR-Rosetta 方法来确定结构。我们强调了使 VISTA 的免疫球蛋白可变（IgV）样折叠在 B7 家族成员中独一无二的特征，包括两个额外的二硫键和一个带有附加螺旋的扩展环区，我们证明该环区形成了与临床相关的抗 VISTA 抗体的连续结合表位。我们提出该抗体结合区域与 V 集和 Ig 域包含 3（VSIG3）的结合表位重叠，VSIG3 是 VISTA 的假定功能结合伙伴。此处呈现的结构和功能表位将有助于指导针对该重要检查点靶标的未来药物开发工作。
