The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors
The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors
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DOI：
10.1073/pnas.0712278105
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发表时间：
2008-02-26
影响因子：
11.1
通讯作者：
Garboczi, David N.
中科院分区：
文献类型：
--
作者：
Lin, David Yin-Wei;Tanaka, Yoshimasa;Garboczi, David N.
程序性死亡受体1（PD - 1）与其配体PD - L1结合后发出的信号可抑制针对自身抗原和肿瘤的免疫反应，并且在维持外周免疫耐受中起重要作用。在慢性病毒感染中，从PD - 1抑制性信号传导中解脱出来可使“耗竭”的病毒特异性T细胞恢复活力。在此我们展示了小鼠PD - 1与人PD - L1复合物的晶体结构。PD - 1和PD - L1通过其免疫球蛋白可变区（IgV）结构域的保守正面和侧面相互作用，抗体和T细胞受体的IgV结构域也是如此。这使得IgV结构域末端的环位于PD - 1/PD - L1复合物的同一侧，形成一个类似于抗体和T细胞受体的抗原结合表面。对保守残基进行定位使得能够识别在形成PD - 1/PD - L1界面中起重要作用的残基。基于该结构，我们表明一些已报道的结合缺失突变涉及PD - 1/PD - L1相互作用，但其他突变则影响蛋白质折叠。此处描述的PD - 1/PD - L1相互作用可被抗体或设计的小分子药物阻断，以降低抑制性信号传导，从而产生更强的免疫反应。免疫受体样环为进一步研究以及潜在地设计影响PD - 1/PD - L1复合物形成从而调节免疫反应的分子提供了一个新的表面。
Signaling through the programmed death 1 (PD-1) inhibitory receptor upon binding its ligand, PD-L1, suppresses immune responses against autoantigens and tumors and plays an important role in the maintenance of peripheral immune tolerance. Release from PD-1 inhibitory signaling revives "exhausted" virus-specific T cells in chronic viral infections. Here we present the crystal structure of murine PD-1 in complex with human PD-L1. PD-1 and PD-L1 interact through the conserved front and side of their Ig variable (IgV) domains, as do the IgV domains of antibodies and T cell receptors. This places the loops at the ends of the IgV domains on the same side of the PD-1/PD-L1 complex, forming a surface that is similar to the antigen-binding surface of antibodies and T cell receptors. Mapping conserved residues allowed the identification of residues that are important in forming the PD-1/PD-L1 interface. Based on the structure, we show that some reported loss-of-binding mutations involve the PD-1/PD-L1 interaction but that others compromise protein folding. The PD-1/PD-L1 interaction described here may be blocked by antibodies or by designed small-molecule drugs to lower inhibitory signaling that results in a stronger immune response. The immune receptor-like loops offer a new surface for further study and potentially the design of molecules that would affect PD-1/PD-L1 complex formation and thereby modulate the immune response.