Molecular System Biology Department, Center of Molecular Immunology, Havana, Havana 11600, Cuba.
Center for Molecular Simulations, Biological Science Department, University of Calgary, Calgary, Alberta T2N 1N4, Canada.
J Phys Chem B. 2022 Feb 24;126(7):1441-1446. doi: 10.1021/acs.jpcb.1c09463. Epub 2022 Feb 15.
The activation of T cells is normally accompanied by inhibitory mechanisms within which the PD1 receptor stands out. PD1 drives T cells to an unresponsive state called exhaustion, characterized by a markedly decreased capacity to exert effector functions upon binding the ligands PDL1 and PDL2. For this reason, PD1 has become one of the most important targets in cancer immunotherapy. Despite the numerous studies about PD1 signaling modulation, how the PD1 signaling pathway is activated upon the ligands' binding remains an open question. In this work, we used molecular dynamics simulations to assess the differences of the PD1 motion in the free state and in complex with the ligands. We found that, in both human and murine systems, the binding of PDL1 and PDL2 stabilizes the conformation of the FG loop similarly. This result, combined with the conservation of the FG loop residues across species, suggests that the conformation of the FG loop is somehow related to the signaling process. We also found a high similarity between the PD1-PDL1 structures with the variable region of an antibody structure, where the FG loop occupies a similar position to the CDR3 light chain.
T 细胞的激活通常伴随着抑制机制，其中 PD1 受体尤为突出。PD1 使 T 细胞进入一种无反应状态，称为衰竭，其特征是在结合配体 PDL1 和 PDL2 时，效应功能的能力明显下降。出于这个原因，PD1 已成为癌症免疫疗法中最重要的靶点之一。尽管有许多关于 PD1 信号转导调节的研究，但配体结合后 PD1 信号通路如何被激活仍然是一个悬而未决的问题。在这项工作中，我们使用分子动力学模拟来评估 PD1 在游离状态和与配体结合时的运动差异。我们发现，在人和鼠系统中，PDL1 和 PDL2 的结合以相似的方式稳定 FG 环的构象。这一结果，加上 FG 环残基在物种间的保守性，表明 FG 环的构象与信号转导过程有关。我们还发现 PD1-PDL1 结构与抗体结构的可变区之间具有高度相似性，其中 FG 环占据与 CDR3 轻链相似的位置。
