Zhao Zi-Jing, Gao Xin-Ying, Zeng Jia-Cheng, Zhang Shao-Long, Meng Xian-Mai, Shen Yan-Jun, Sheng Xie-Huang
College of Chemistry, Chemical Engineering and Materials Science, Shandong Normal University, Jinan, Shandong 250014, China.
College of Physics and Electronics, Shandong Normal University, 88 Wenhuadonglu, Jinan, Shandong 250014, China.
J Phys Chem B. 2020 Nov 5;124(44):9803-9811. doi: 10.1021/acs.jpcb.0c06662. Epub 2020 Oct 25.
The multidrug resistance protein MRP1 is an ATP binding cassette (ABC) transporter that confers resistance to many anticancer drugs and regulates redox homeostasis, inflammation, and hormone secretion. MRP1 actively transports compounds across cell membranes, and the presence of glutathione (GSH) is required in many cases. However, the process of MRP1-mediated substrate transportation has been poorly understood. With extensive molecular dynamics simulations, we have found a sandwich-like structure which is generated by GSH, a transmembrane α-helices 11 (TM11)-TM17 axis, and anticancer drugs. This structure is crucial in MRP1 transportation. It triggers the motion of TM11 and TM17, followed by the movement of nucleotide-binding domains 1 (NBD1) and 2 (NBD2), and finally an occluded structure is formed. Trp1246, Lys332, and Phe594 were identified as the main contributors in the formation of the sandwich-like structure. Our findings clearly explain the synergy of GSH with an anticancer drug in MRP1 transportation and have significant meanings for the rational design of novel inhibitors against MRP1.
多药耐药蛋白MRP1是一种ATP结合盒（ABC）转运蛋白，它赋予细胞对多种抗癌药物的抗性，并调节氧化还原稳态、炎症和激素分泌。MRP1能主动将化合物转运穿过细胞膜，在许多情况下都需要谷胱甘肽（GSH）的存在。然而，人们对MRP1介导的底物运输过程了解甚少。通过广泛的分子动力学模拟，我们发现了一种由GSH、跨膜α螺旋11（TM11）-TM17轴和抗癌药物形成的三明治样结构。这种结构在MRP1运输中至关重要。它触发TM11和TM17的运动，随后是核苷酸结合结构域1（NBD1）和2（NBD2）的移动，最终形成一种封闭结构。色氨酸1246、赖氨酸332和苯丙氨酸594被确定为形成三明治样结构的主要贡献者。我们的研究结果清楚地解释了GSH与抗癌药物在MRP1运输中的协同作用，对合理设计新型MRP1抑制剂具有重要意义。
