The Alternating Access Mechanism in Mammalian Multidrug Resistance Transporters and Their Bacterial Homologs.
The Alternating Access Mechanism in Mammalian Multidrug Resistance Transporters and Their Bacterial Homologs.
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DOI：
10.3390/membranes13060568
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发表时间：
2023-05-30
期刊：
影响因子：
4.2
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中科院分区：
文献类型：
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多药耐药(MDR)蛋白属于三磷酸腺苷结合盒(ABC)转运体，在细胞毒药物跨细胞膜输出过程中起着至关重要的作用。这些蛋白质尤其令人着迷，因为它们能够产生耐药性，从而导致治疗干预失败，阻碍成功的治疗。多药耐药(MDR)蛋白实现其转运功能的一个关键机制是通过交替进入。这一机制涉及复杂的构象变化，使底物能够结合和跨细胞膜运输。在这篇广泛的综述中，我们提供了ABC转运蛋白的概述，包括它们的分类和结构上的相似性。我们特别关注众所周知的哺乳动物多药耐药蛋白，如MRP1和Pgp(Mdr1)，以及细菌对应蛋白，如Sav1866和脂质翻转酶MSBA。通过探索这些MDR蛋白的结构和功能特征，我们揭示了它们的核苷酸结合域(NBD)和跨膜域(TMDs)在转运过程中的作用。值得注意的是，虽然原核生物ABC蛋白(如Sav1866、MSBA和哺乳动物Pgp)中NBD的结构相同，但MRP1的NBDS显示出不同的特征。我们的综述还强调了两个ATP分子对于在所有这些转运蛋白上的NBD结构域的两个结合位点之间形成界面的重要性。ATP水解酶在底物运输之后发生，在随后的底物运输循环中对转运蛋白的循环至关重要。具体地说，在所研究的转运体中，只有MRP1中的Nbd2具有水解ATP的能力，而Pgp的Nbd2、Sav1866和MSBA都能够进行这一反应。此外，我们重点介绍了MDR蛋白和交替访问机制研究的最新进展。我们讨论了用于研究MDR蛋白的结构和动力学的实验和计算方法，为其构象变化和底物运输提供了有价值的见解。这篇综述不仅有助于加深对多药耐药蛋白的了解，而且具有指导未来研究和促进制定有效策略克服多药耐药的巨大潜力，从而改进治疗干预措施。
Multidrug resistance (MDR) proteins belonging to the ATP-Binding Cassette (ABC) transporter group play a crucial role in the export of cytotoxic drugs across cell membranes. These proteins are particularly fascinating due to their ability to confer drug resistance, which subsequently leads to the failure of therapeutic interventions and hinders successful treatments. One key mechanism by which multidrug resistance (MDR) proteins carry out their transport function is through alternating access. This mechanism involves intricate conformational changes that enable the binding and transport of substrates across cellular membranes. In this extensive review, we provide an overview of ABC transporters, including their classifications and structural similarities. We focus specifically on well-known mammalian multidrug resistance proteins such as MRP1 and Pgp (MDR1), as well as bacterial counterparts such as Sav1866 and lipid flippase MsbA. By exploring the structural and functional features of these MDR proteins, we shed light on the roles of their nucleotide-binding domains (NBDs) and transmembrane domains (TMDs) in the transport process. Notably, while the structures of NBDs in prokaryotic ABC proteins, such as Sav1866, MsbA, and mammalian Pgp, are identical, MRP1 exhibits distinct characteristics in its NBDs. Our review also emphasizes the importance of two ATP molecules for the formation of an interface between the two binding sites of NBD domains across all these transporters. ATP hydrolysis occurs following substrate transport and is vital for recycling the transporters in subsequent cycles of substrate transportation. Specifically, among the studied transporters, only NBD2 in MRP1 possesses the ability to hydrolyze ATP, while both NBDs of Pgp, Sav1866, and MsbA are capable of carrying out this reaction. Furthermore, we highlight recent advancements in the study of MDR proteins and the alternating access mechanism. We discuss the experimental and computational approaches utilized to investigate the structure and dynamics of MDR proteins, providing valuable insights into their conformational changes and substrate transport. This review not only contributes to an enhanced understanding of multidrug resistance proteins but also holds immense potential for guiding future research and facilitating the development of effective strategies to overcome multidrug resistance, thus improving therapeutic interventions.
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