Department of Chemistry and Soft Matter Research Center, Zhejiang University, Hangzhou 310027, People's Republic of China.
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China.
Phys Chem Chem Phys. 2021 Mar 4;23(8):4530-4543. doi: 10.1039/d0cp05910b.
P-glycoprotein (P-gp), a member of ATP-binding cassette (ABC) transporters, is a multidrug resistance pump. Its promiscuous nature is the main cause of multidrug resistance in cancer cells. P-gp can bind multiple drug molecules simultaneously; however, the binding mechanism is still not clear. Furthermore, the upper limit of the number of substrates that can be accommodated by the binding pocket is not fully understood. In this work, we explore the dynamic process of P-gp binding to multiple substrates by using molecular dynamics (MD) simulations. Our results show that P-gp possesses the ability for simultaneous binding, and that the number of substrates has an upper limit. The accommodating ability of P-gp relates to the size of the binding drugs, and conforms to induced fit theory. In the binding process, the residues 339PHE, 982MET and 986GLN are essential. The pocket of P-gp presents strong flexibility and adaptability features according to the mutation results in this work. Drug molecules tend to gather in the pocket during binding, and interactions between these molecules are beneficial to simultaneous binding. These findings provide new insights into the mechanism of the promiscuous nature of P-gp, and may give us a guideline for inhibiting the process of multidrug resistance.
P-糖蛋白（P-gp）是 ATP 结合盒（ABC）转运体的成员，是一种多药耐药泵。其混杂的性质是癌细胞多药耐药的主要原因。P-gp 可以同时结合多个药物分子；然而，其结合机制尚不清楚。此外，结合口袋可容纳的底物数量的上限也不完全清楚。在这项工作中，我们通过分子动力学（MD）模拟探索了 P-gp 与多个底物结合的动态过程。我们的结果表明，P-gp 具有同时结合的能力，并且底物的数量存在上限。P-gp 的容纳能力与结合药物的大小有关，符合诱导契合理论。在结合过程中，339PHE、982MET 和 986GLN 残基是必需的。根据这项工作中的突变结果，P-gp 的口袋具有很强的灵活性和适应性特征。在结合过程中，药物分子倾向于聚集在口袋中，并且这些分子之间的相互作用有利于同时结合。这些发现为 P-gp 混杂性质的机制提供了新的见解，并可能为我们抑制多药耐药过程提供指导。
