School of Life Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, China.
Cell Commun Signal. 2018 Jun 7;16(1):25. doi: 10.1186/s12964-018-0239-9.
Programmed cell death protein 1 (PD-1), a negative co-stimulatory molecule, plays crucial roles in immune escape. Blockade of the interaction between PD-1 and PD-L1 shows exciting clinical responses in a fraction of cancer patients and the success makes PD-1 as a valuable target in immune checkpoint therapy. For the rational design of PD-1 targeting modulators, the ligand binding mechanism of PD-1 should be well understood in prior.
In this study, we applied 50 ns molecular dynamics simulations to observe the structural properties of PD-1 molecule in both apo and ligand bound states, and we studied the structural features of PD-1 in human and mouse respectively.
The results showed that the apo hPD-1 was more flexible than that in PD-L1 bound state. We unexpectedly found that K135 was important for binding energy although it was not at the binding interface. Moreover, the residues which stabilized the interactions with PD-L1 were distinguished. Taking the dynamic features of these residues into account, we identified several residual sites where mutations may gain the function of ligand binding. The in vitro binding experiments revealed the mutants M70I, S87 W, A129L, A132L, and K135 M were better in ligand binding than the wild type PD-1.
The structural information from MD simulation combined with in silico mutagenesis provides guidance to design engineered PD-1 mutants to modulate the PD-1/PD-L1 pathway.
程序性死亡蛋白 1（PD-1）是一种负性共刺激分子，在免疫逃逸中发挥着重要作用。阻断 PD-1 与 PD-L1 之间的相互作用，在一部分癌症患者中显示出令人兴奋的临床反应，这一成功使 PD-1 成为免疫检查点治疗的一个有价值的靶点。为了合理设计 PD-1 靶向调节剂，首先需要深入了解 PD-1 的配体结合机制。
在这项研究中，我们应用了 50ns 的分子动力学模拟来观察 PD-1 分子在apo 和配体结合状态下的结构特性，并分别研究了 PD-1 在人和小鼠中的结构特征。
结果表明，apo hPD-1 比与 PD-L1 结合状态下的 PD-1 更具柔性。我们意外地发现，尽管 K135 不在结合界面上，但它对结合能很重要。此外，还区分了稳定与 PD-L1 相互作用的残基。考虑到这些残基的动态特征，我们确定了几个残基位点，突变可能获得配体结合的功能。体外结合实验表明，突变体 M70I、S87W、A129L、A132L 和 K135M 在配体结合方面优于野生型 PD-1。
MD 模拟的结构信息结合计算机诱变提供了设计工程化 PD-1 突变体以调节 PD-1/PD-L1 途径的指导。
