Inserm U1248 Pharmacology & Transplantation, ΩHealth Institute-Univ. Limoges, 2 rue du Prof. Descottes, 87000 F, Limoges, France.
Commun Biol. 2023 Feb 3;6(1):149. doi: 10.1038/s42003-023-04537-3.
Multidrug resistance-associated proteins are ABC C-family exporters. They are crucial in pharmacology as they transport various substrates across membranes. However, the role of the degenerate nucleotide-binding site (NBS) remains unclear likewise the interplay with the surrounding lipid environment. Here, we propose a dynamic and structural overview of MRP1 from ca. 110 μs molecular dynamics simulations. ATP binding to NBS1 is likely maintained along several transport cycles. Asymmetric NBD behaviour is ensured by lower signal transduction from NBD1 to the rest of the protein owing to the absence of ball-and-socket conformation between NBD1 and coupling helices. Even though surrounding lipids play an active role in the allosteric communication between the substrate-binding pocket and NBDs, our results suggest that lipid composition has a limited impact, mostly by affecting transport kinetics. We believe that our work can be extended to other degenerate NBS ABC proteins and provide hints for deciphering mechanistic differences among ABC transporters.
多药耐药相关蛋白是 ABC C 家族的外排泵。它们在药理学中至关重要，因为它们可以将各种底物跨膜运输。然而，退化核苷酸结合位点（NBS）的作用同样不清楚，与周围脂质环境的相互作用也不清楚。在这里，我们从约 110 μs 的分子动力学模拟中提出了 MRP1 的动态和结构概述。ATP 与 NBS1 的结合可能在几个运输循环中得以维持。由于 NBD1 与偶联螺旋之间不存在球窝构象，因此 NBD1 向蛋白质其余部分的信号转导较低，从而确保了非对称 NBD 行为。尽管周围的脂质在底物结合口袋和 NBD 之间的变构通讯中发挥着积极的作用，但我们的结果表明，脂质组成的影响有限，主要是通过影响运输动力学。我们相信我们的工作可以扩展到其他退化的 NBS ABC 蛋白，并为解析 ABC 转运蛋白之间的机制差异提供线索。
