免疫检查点受体 PD-1 及其配体 PD-L1/PD-L2 的结构生物学。

Structural Biology of the Immune Checkpoint Receptor PD-1 and Its Ligands PD-L1/PD-L2.

机构信息

Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7a, 30-387 Krakow, Poland; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland.

Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland.

出版信息

Structure. 2017 Aug 1;25(8):1163-1174. doi: 10.1016/j.str.2017.06.011.

DOI:10.1016/j.str.2017.06.011

PMID:28768162

Abstract

Cancer cells can avoid and suppress immune responses through activation of inhibitory immune checkpoint proteins, such as PD-1, PD-L1, and CTLA-4. Blocking the activities of these proteins with monoclonal antibodies, and thus restoring T cell function, has delivered breakthrough therapies against cancer. In this review, we describe the latest work on structural characterization of the checkpoint proteins, their interactions with cognate ligands and with therapeutic antibodies. Structures of the extracellular portions of these proteins reveal that they all have a similar modular structure, composed of small domains similar in topology to the domains found in antibodies. Structural basis for blocking the PD-1/PD-L1 interaction by small molecules is illustrated with the compound BMS-202 that binds to and induces dimerization of PD-L1.

摘要

癌细胞可以通过激活抑制性免疫检查点蛋白（如 PD-1、PD-L1 和 CTLA-4）来逃避和抑制免疫反应。用单克隆抗体阻断这些蛋白的活性，从而恢复 T 细胞功能，为癌症治疗带来了突破性的疗法。在这篇综述中，我们描述了检查点蛋白的结构特征、它们与同源配体以及与治疗性抗体相互作用的最新研究工作。这些蛋白的细胞外部分的结构表明，它们都具有相似的模块结构，由拓扑结构与抗体中发现的结构相似的小结构域组成。小分子阻断 PD-1/PD-L1 相互作用的结构基础通过结合并诱导 PD-L1 二聚化的化合物 BMS-202 得到了说明。