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Computational analysis of hot spots and binding mechanism in the PD-1/PD-L1 interaction

机译：PD-1 / PD-L1相互作用中热点和绑定机制的计算分析

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摘要

Programmed cell death protein-1 (PD-1) is an important immunological checkpoint and plays a vital role in maintaining the peripheral tolerance of the human body by interacting with its ligand PD-L1. The overexpression of PD-L1 in tumor cells induces local immune suppression and helps the tumor cells to evade the endogenous anti-tumor immunity. Developing monoclonal antibodies against the PD-1/PD-L1 protein-protein interaction to block the PD-1/PD-L1 signaling pathway has demonstrated superior anti-tumor efficacy in a variety of solid tumors and has made a profound impact on the field of cancer immunotherapy in recent years. Although the X-ray crystal structure of the PD-1/PD-L1 complex has been solved, the detailed binding mechanism of the PD-1/PD-L1 interaction is not fully understood from a theoretical point of view. In this study, we performed computational alanine scanning on the PD-1/PD-L1 complex to quantitatively identify the hot spots in the PD-1/PD-L1 interaction and characterize its binding mechanisms at the atomic level. To the best of our knowledge, this is the first time that theoretical calculations have been used to systematically and quantitatively predict the hot spots in the PD-1/PD-L1 interaction. We hope that the predicted hot spots and the energy profile of the PD-1/PD-L1 interaction presented in this work can provide guidance for the design of peptide and small molecule drugs targeting PD-1 or PD-L1.
机译：编程的细胞死亡蛋白-1（PD-1）是重要的免疫检查点，并在通过与其配体PD-L1相互作用来保持人体的外周耐受性至关重要。 PD-L1在肿瘤细胞中的过度表达诱导局部免疫抑制，有助于肿瘤细胞避免内源性抗肿瘤免疫。对PD-1 / PD-L1蛋白质 - 蛋白质 - 蛋白质 - 蛋白 - 蛋白质相互作用的开发单克隆抗体在各种固体瘤中表现出优异的抗肿瘤效果，并对该领域产生了深远的影响近年来癌症免疫疗法。尽管已经解决了PD-1 / PD-L1络合物的X射线晶体结构，但是从理论的观点来看，不完全理解PD-1 / PD-L1相互作用的详细结合机制。在本研究中，我们在PD-1 / PD-L1复合物上进行计算丙氨酸扫描，以定量地识别PD-1 / PD-L1相互作用中的热点，并在原子水平上表征其结合机制。据我们所知，这是第一次首次用于系统和定量地预测PD-1 / PD-L1相互作用中的热点。我们希望在该工作中提出的预测的热点和PD-1 / PD-L1相互作用的能量轮廓可以为靶向PD-1或PD-L1的肽和小分子药物的设计提供指导。

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  • 来源
    《RSC Advances》 |2019年第26期|共13页
  • 作者

    Huang Dading; Wen Wei; Liu Xiao; Li Yang; Zhang John Z. H.;

  • 作者单位

    East China Normal Univ Sch Chem &

    Mol Engn Shanghai Engn Res Ctr Mol Therapeut &

    New Drug De State Key Lab Precis Spect Shanghai 200062 Peoples R China;

    East China Normal Univ Sch Chem &

    Mol Engn Shanghai Engn Res Ctr Mol Therapeut &

    New Drug De State Key Lab Precis Spect Shanghai 200062 Peoples R China;

    East China Normal Univ Sch Chem &

    Mol Engn Shanghai Engn Res Ctr Mol Therapeut &

    New Drug De State Key Lab Precis Spect Shanghai 200062 Peoples R China;

    East China Normal Univ Sch Chem &

    Mol Engn Shanghai Engn Res Ctr Mol Therapeut &

    New Drug De State Key Lab Precis Spect Shanghai 200062 Peoples R China;

    East China Normal Univ Sch Chem &

    Mol Engn Shanghai Engn Res Ctr Mol Therapeut &

    New Drug De State Key Lab Precis Spect Shanghai 200062 Peoples R China;

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  • 正文语种 eng
  • 中图分类 化学;
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