ABC Transporters - 40 Years on
ABC Transporters - 40 Years on
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ABC Transporters - 40 周年
DOI：
10.1007/978-3-319-23476-2_2
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Van Veen H
中科院分区：
文献类型：
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作者：
Van Veen H
细菌ATP结合盒（ABC）出口商涵盖了大量的生物过程。它们可以介导从小的无机离子、药物和抗生素到大的蛋白质毒素和其他大分子的各种底物的外排。它们也可以在跨膜信号转导过程中作为介导剂和调节剂，可能不介导任何直接的转运反应。ABC出口商功能的这种多样性提出了关于其结构，构象变化如何与活性相结合以及我们如何使用这些信息来抑制，激活或绕过基于药物的策略中的生理功能的问题。当第一个ABC转运蛋白被发现时，现在是40年前，通过序列比较，人们注意到它们中的许多人共享相似的结构域组织。但这些区域究竟如何在介导运输活动中合作尚不清楚。大量的生化研究和核苷酸结合域（NBD）的晶体结构，以及随后的全长ABC出口商，表明一般的机制是基于代谢能量依赖性的交替访问的底物结合口袋（S）的磷脂双层的任一侧，但有正在采用的详细的分子机制的多样性。本章概述了在过去几年中出现的结构和机制的复杂性，以及对这些惊人的转运蛋白进行进一步研究的挑战。
Bacterial ATP-binding cassette (ABC) exporters embrace an enormous range of biological processes. They can mediate the efflux of a wide variety of substrates ranging from small inorganic ions, drugs, and antibiotics to large protein toxins and other macromolecules. They can also act as mediators and regulators in transmembrane signaling processes perhaps without mediating any direct transport reaction. This diversity in function of ABC exporters raises questions about their structure, how conformational changes are coupled to activity, and how we can use this information to inhibit, activate, or bypass physiological functions in drug-based strategies. When the first ABC transporters were discovered, now 40 years ago, it was noted by sequence comparisons that many of them shared a similar domain organization. But exactly how these domains cooperate in mediating transport activity was unknown. A wealth of biochemical studies and crystal structures of nucleotide-binding domains (NBDs), and subsequently of full-length ABC exporters, suggests that the general mechanism is based on metabolic energy-dependent alternating access of substrate-binding pocket(s) to either side of the phospholipid bilayer, but that there is diversity in the detailed molecular mechanisms that are being employed. This chapter provides an overview of the structural and mechanistic intricacies that have surfaced over the past years, and the challenges in further studies on these amazing transport proteins.