Seelig Anna, Li-Blatter Xiaochun
Biozentrum, University of Basel, Basel 4056, Switzerland.
Cancer Drug Resist. 2023 Jan 1;6(1):1-29. doi: 10.20517/cdr.2022.59. eCollection 2023.
P-glycoprotein (ABCB1) is the first discovered mammalian member of the large family of ATP binding cassette (ABC) transporters. It facilitates the movement of compounds (called allocrites) across membranes, using the energy of ATP binding and hydrolysis. Here, we review the thermodynamics of allocrite binding and the kinetics of ATP hydrolysis by ABCB1. In combination with our previous molecular dynamics simulations, these data lead to a new model for allocrite transport by ABCB1. In contrast to previous models, we take into account that the transporter was evolutionarily optimized to operate within a membrane, which dictates the nature of interactions. Hydrophobic interactions drive lipid-water partitioning of allocrites, the transport process's first step. Weak dipolar interactions (including hydrogen bonding, π-π stacking, and π-cation interactions) drive allocrite recognition, binding, and transport by ABCB1 within the membrane. Increasing the lateral membrane packing density reduces allocrite partitioning but enhances dipolar interactions between allocrites and ABCB1. Allocrite flopping (or reorientation of the polar part towards the extracellular aqueous phase) occurs after hydrolysis of one ATP molecule and opening of ABCB1 at the extracellular side. Rebinding of ATP re-closes the transporter at the extracellular side and expels the potentially remaining allocrite into the membrane. The high sensitivity of the steady-state ATP hydrolysis rate to the nature and number of dipolar interactions, as well as to the dielectric constant of the membrane, points to a flopping process, which occurs to a large extent at the membrane-transporter interface. The proposed unidirectional ABCB1 transport cycle, driven by weak dipolar interactions, is consistent with membrane biophysics.
P-糖蛋白（ABCB1）是ATP结合盒（ABC）转运蛋白大家族中首个被发现的哺乳动物成员。它利用ATP结合和水解产生的能量，促进化合物（称为配体）跨膜转运。在此，我们综述了ABCB1介导的配体结合热力学和ATP水解动力学。结合我们之前的分子动力学模拟，这些数据得出了一个ABCB1介导的配体转运新模型。与之前的模型不同，我们考虑到转运蛋白在进化过程中经过优化，以便在膜内发挥作用，这决定了相互作用的性质。疏水相互作用驱动配体在脂质-水之间的分配，这是转运过程的第一步。弱偶极相互作用（包括氢键、π-π堆积和π-阳离子相互作用）驱动ABCB1在膜内对配体的识别、结合和转运。增加膜的侧向堆积密度会降低配体的分配，但会增强配体与ABCB1之间的偶极相互作用。在一个ATP分子水解且ABCB1在细胞外侧打开后，配体发生翻转（或极性部分重新定向至细胞外水相）。ATP的重新结合会在细胞外侧重新关闭转运蛋白，并将可能残留的配体排出至膜内。稳态ATP水解速率对偶极相互作用的性质和数量以及膜的介电常数高度敏感，这表明翻转过程在很大程度上发生在膜-转运蛋白界面。所提出的由弱偶极相互作用驱动的单向ABCB1转运循环与膜生物物理学一致。
