基于计算丙氨酸扫描的 PD-L1 与其单克隆抗体的残基特异性结合机制。

Residue-specific binding mechanisms of PD-L1 to its monoclonal antibodies by computational alanine scanning.

机构信息

Shanghai Engineering Research Center of Molecular Therapeutics & New Drug Development, Shanghai Key Laboratory of Green Chemistry & Chemical Process, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China.

出版信息

Phys Chem Chem Phys. 2021 Jul 28;23(29):15591-15600. doi: 10.1039/d1cp01281a.

DOI:10.1039/d1cp01281a

PMID:34259259

Abstract

Programmed cell death 1 receptor (PD-1) on the surface of T cells and its ligand 1 (PD-L1) are immune checkpoint proteins. Treating cancer patients with inhibitors blocking this checkpoint has significantly prolonged the survival rate of patients. In this study, we examined several monoclonal antibodies (mAbs) of PD-L1 and studied their detailed binding mechanism to PD-L1. An efficient computational alanine scanning method was used to perform quantitative analysis of hotspot residues that are important for PD-1/PD-L1 binding. A total of five PD-L1/mAb complexes were investigated and hotspots on both PD-L1 and mAbs were predicted. Our result shows that PD-L1M115 and PD-L1Y123 are two relatively important hotspots in all the five PD-L1/mAb binding complexes. It is also found that the important residues of mAbs binding to PD-L1M115 and PD-L1Y123 are similar to each other. The computational alanine scanning result is compared to the experimental measurements that are available for two of the mAbs (KN035 and atezolizumab). The calculated alanine scanning result is in good agreement with the experimental data with a correlation coefficient of 0.87 for PD-L1/KN035 and 0.6 for PD-L1/atezolizumab. Our computation found more hotspots on PD-L1 in the PD-L1/KN035 complex than those in the PD-L1/atezolizumab system, indicating stronger binding affinity in the former than the latter, which is in good agreement with the experimental finding. The present work provides important insights for the design of new mAbs targeting PD-L1.

摘要

程序性细胞死亡受体 1（PD-1）在 T 细胞表面及其配体 1（PD-L1）是免疫检查点蛋白。用抑制该检查点的抑制剂治疗癌症患者显著延长了患者的生存率。在这项研究中，我们研究了几种 PD-L1 的单克隆抗体（mAbs），并研究了它们与 PD-L1 的详细结合机制。使用有效的计算丙氨酸扫描方法对 PD-1/PD-L1 结合中重要的热点残基进行定量分析。总共研究了五个 PD-L1/mAb 复合物，并预测了 PD-L1 和 mAb 上的热点。我们的结果表明，在所有五个 PD-L1/mAb 结合复合物中，PD-L1M115 和 PD-L1Y123 是两个相对重要的热点。还发现，mAbs 与 PD-L1M115 和 PD-L1Y123 结合的重要残基彼此相似。计算的丙氨酸扫描结果与两个 mAbs（KN035 和 atezolizumab）的实验测量值进行了比较。计算的丙氨酸扫描结果与实验数据吻合良好，PD-L1/KN035 的相关系数为 0.87，PD-L1/atezolizumab 的相关系数为 0.6。我们的计算结果发现，在 PD-L1/KN035 复合物中，PD-L1 上的热点比 PD-L1/atezolizumab 系统中的热点多，这表明前者的结合亲和力强于后者，这与实验结果一致。这项工作为设计针对 PD-L1 的新型 mAb 提供了重要的见解。