Crystal structure of the complex between programmed death-1 (PD-1) and its ligand PD-L2
Crystal structure of the complex between programmed death-1 (PD-1) and its ligand PD-L2
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DOI：
10.1073/pnas.0804453105
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发表时间：
2008-07-29
影响因子：
11.1
通讯作者：
Almo, Steven C.
中科院分区：
文献类型：
--
作者：
Lazar-Molnar, Eszter;Yan, Qingrong;Almo, Steven C.
程序性死亡受体1（PD - 1）是CD28 / B7超家族的成员，在与其两种配体PD - L1或PD - L2相互作用时传递负性信号。小鼠PD - 1和PD - L2完整胞外结构域形成的复合物的高分辨率晶体结构显示受体与配体化学计量比为1∶1，并呈现出与CTLA - 4 / B7抑制性复合物中所观察到的不同的结合界面和整体分子构象。此外，我们的结构还为PD - 1和PD - L1之间的结合提供了见解，并突出了两种PD - 1配体（PD - Ls）所形成界面的差异。诱变研究证实了所提出的PD - 1 / PD - L结合界面的细节，并使得能够设计出一种具有增强亲和力的突变型PD - 1受体。这些研究确定了控制免疫突触内PD - 1 / PD - L复合物的定位和信号传导的空间和组织限制，并为操纵用于免疫治疗的PD - 1通路提供了基础。
Programmed death-1 (PD-1) is a member of the CD28/B7 superfamily that delivers negative signals upon interaction with its two ligands, PD-L1 or PD-L2. The high-resolution crystal structure of the complex formed by the complete ectodomains of murine PD-1 and PD-L2 revealed a 1:1 receptor:ligand stoichiometry and displayed a binding interface and overall molecular organization distinct from that observed in the CTLA-4/B7 inhibitory complexes. Furthermore, our structure also provides insights into the association between PD-1 and PD-L1 and highlights differences in the interfaces formed by the two PD-1 ligands (PD-Ls) Mutagenesis studies confirmed the details of the proposed PD-1/PD-L binding interfaces and allowed for the design of a mutant PD-1 receptor with enhanced affinity. These studies define spatial and organizational constraints that control the localization and signaling of PD-1/PD-L complexes within the immunological synapse and provide a basis for manipulating the PD-1 pathways for immunotherapy.