Ahmed Marawan, Barakat Khaled
Faculty of Pharmacy and Pharmaceutical Sciences, and ‡Li Ka Shing Institute of Virology, University of Alberta , Edmonton, Alberta, Canada.
Biochemistry. 2017 Oct 10;56(40):5428-5439. doi: 10.1021/acs.biochem.7b00655. Epub 2017 Sep 25.
In the current study, we focused on the immune-checkpoints PD-1 pathway and in particular on the ligand PD-L1. We studied the conformational dynamics of PD-L1 through principal component analysis of existing crystal structures combined with classical and accelerated molecular dynamics simulations. We identified the maximum structural displacements that take place in all PD-L1 crystal structures and in the molecular dynamics trajectories. We found that these displacements are attributed to specific flexible regions in the protein. We also investigated the conformational preference for small molecule binding and highlighted a methionine residue at the binding site, which plays a key role in drug binding. The binding mechanism of PD-L1 to other binding partners is also discussed in detail from a computational perspective. We hope that the data presented here support the ongoing efforts to discover effective therapies targeting the PD-1 immune-checkpoint pathway.
在当前的研究中，我们聚焦于免疫检查点PD-1通路，尤其关注配体PD-L1。我们通过对现有晶体结构进行主成分分析，并结合经典和加速分子动力学模拟，研究了PD-L1的构象动力学。我们确定了在所有PD-L1晶体结构和分子动力学轨迹中发生的最大结构位移。我们发现这些位移归因于蛋白质中的特定柔性区域。我们还研究了小分子结合的构象偏好，并突出了结合位点处的一个甲硫氨酸残基，它在药物结合中起关键作用。从计算角度详细讨论了PD-L1与其他结合伙伴的结合机制。我们希望这里呈现的数据能够支持正在进行的针对PD-1免疫检查点通路发现有效疗法的努力。
