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预测PD1-PDL1复合物的稳定二进制形式:理解PD1激活机制的含义

Luis F Ponce^1,2, Daniel P Ramírez-Echemendia¹, Kalet León²

¹Center for Molecular Simulations, Biological Science Department, University of Calgary, Calgary, Alberta D2N 1N4, Canada.

The journal of physical chemistry. B

|June 21, 2023

概括

编程细胞死亡蛋白1 (PD1) 信号传导,在癌症免疫治疗中至关重要,可能会被PD1-PDL1二分体激活. 这种二聚体形成可以使下游信号传递,解释PD1-PDL1抗体如何抑制T细胞耗尽.

科学领域:

免疫学免疫学免疫学
分子生物学分子生物学
计算生物学计算生物学

背景情况:

编程细胞死亡蛋白1 (PD1) 是T细胞的关键抑制受体,诱导疲劳并限制抗瘤免疫力.
由其配体PDL1和PDL2触发的PD1信号传递是癌症免疫疗法的主要目标,但其精确的激活机制尚不清楚.
现有研究表明,一个未知的膜合作伙伴调解PD1-PDL1通路的激活.

研究的目的:

为了研究PD1-PDL1复合体本身作为激活伙伴的假设.
阐明PD1-PDL1复合体形成的结构基础及其在信号传导中的作用.
提出PD1受体激活及其通过治疗抗体抑制的新型模型.

主要方法:

利用分子对接来预测PD1-PDL1复合体的潜在结合模式.
采用分子动力学和雨采样模拟来评估复杂的稳定性和结合亲和力.
分析了预测PD1-PDL1复合体的结构特征.

主要成果:

预测了PD1-PDL1复合体细胞外域的稳定二维形式.
二维复合体表现出与单体PD1-PDL1相互作用相似的结合亲和力,并形成一个线性格子状结构.
这种二次构造被建议促进细胞内PD1域相互作用和随后的SHP2酸酶结合和激活.

结论:

PD1-PDL1复合体可以形成稳定的二元体,提供PD1受体激活的潜在机制.
这种二维模型为PD1信号如何通过SHP2酸酶导致T细胞耗尽提供了新的解释.
这些发现表明,抗PD1/PDL1抗体可能通过破坏PD1-PDL1二元体的形成来发挥其抑制作用,从而阻断SHP2激活.

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