Amity Institute of Biotechnology and Amity Institute of Integrative Sciences and Health, Amity University Haryana, Gurugram, India.
Drug Resistance & Membrane Proteins group, CNRS-Lyon 1 University Laboratory 5086, IBCP, Lyon, France.
Drug Resist Updat. 2023 Nov;71:100992. doi: 10.1016/j.drup.2023.100992. Epub 2023 Aug 5.
ATP-binding cassette (ABC) superfamily comprises a large group of ubiquitous transmembrane proteins that play a crucial role in transporting a diverse spectrum of substrates across cellular membranes. They participate in a wide array of physiological and pathological processes including nutrient uptake, antigen presentation, toxin elimination, and drug resistance in cancer and microbial cells. ABC transporters couple ATP binding and hydrolysis to undergo conformational changes allowing substrate translocation. Within this superfamily, a set of ABC transporters has lost the capacity to hydrolyze ATP at one of their nucleotide-binding sites (NBS), called the non-catalytic NBS, whose importance became evident with extensive biochemistry carried out on yeast pleiotropic drug resistance (PDR) transporters. Recent single-particle cryogenic electron microscopy (cryo-EM) advances have further catapulted our understanding of the architecture of these pumps. We provide here a comprehensive overview of the structural and functional aspects of catalytically asymmetric ABC pumps with an emphasis on the PDR subfamily. Furthermore, given the increasing evidence of efflux-mediated antifungal resistance in clinical settings, we also discuss potential grounds to explore PDR transporters as therapeutic targets.
ATP 结合盒（ABC）超家族由一大组普遍存在的跨膜蛋白组成，它们在跨细胞膜运输各种底物方面发挥着关键作用。它们参与了广泛的生理和病理过程，包括营养物质摄取、抗原呈递、毒素消除以及癌症和微生物细胞中的药物耐药性。ABC 转运蛋白通过结合和水解 ATP 来进行构象变化，从而允许底物转运。在这个超家族中，一组 ABC 转运蛋白已经失去了在其核苷酸结合位点（NBS）之一处水解 ATP 的能力，这个 NBS 被称为非催化 NBS，其重要性在对酵母多药耐药（PDR）转运蛋白进行的广泛生物化学研究中变得明显。最近的单颗粒低温电子显微镜（cryo-EM）进展进一步推动了我们对这些泵的结构和功能的理解。我们在这里提供了对催化不对称 ABC 泵的结构和功能方面的全面概述，重点介绍了 PDR 亚家族。此外，鉴于临床环境中抗真菌药物外排介导的耐药性的证据不断增加，我们还讨论了探索 PDR 转运蛋白作为治疗靶点的潜在依据。
