Structural Biology, Genentech Inc., San Francisco, CA, USA.
Biochemical and Cellular Pharmacology, Genentech Inc., San Francisco, CA, USA.
Nature. 2018 May;557(7704):196-201. doi: 10.1038/s41586-018-0083-5. Epub 2018 May 2.
The movement of core-lipopolysaccharide across the inner membrane of Gram-negative bacteria is catalysed by an essential ATP-binding cassette transporter, MsbA. Recent structures of MsbA and related transporters have provided insights into the molecular basis of active lipid transport; however, structural information about their pharmacological modulation remains limited. Here we report the 2.9 Å resolution structure of MsbA in complex with G907, a selective small-molecule antagonist with bactericidal activity, revealing an unprecedented mechanism of ABC transporter inhibition. G907 traps MsbA in an inward-facing, lipopolysaccharide-bound conformation by wedging into an architecturally conserved transmembrane pocket. A second allosteric mechanism of antagonism occurs through structural and functional uncoupling of the nucleotide-binding domains. This study establishes a framework for the selective modulation of ABC transporters and provides rational avenues for the design of new antibiotics and other therapeutics targeting this protein family.
革兰氏阴性菌内膜核心脂多糖的转运是由一种必需的 ATP 结合盒转运蛋白 MsbA 催化的。MsbA 和相关转运蛋白的最近结构提供了对主动脂质转运分子基础的深入了解；然而，关于它们药理学调节的结构信息仍然有限。在这里，我们报告了 MsbA 与 G907 复合物的 2.9Å 分辨率结构，G907 是一种具有杀菌活性的选择性小分子拮抗剂，揭示了 ABC 转运蛋白抑制的一种前所未有的机制。G907 通过楔入结构保守的跨膜口袋，将 MsbA 困在内向脂多糖结合构象中。第二种变构拮抗机制通过核苷酸结合域的结构和功能解耦发生。这项研究为 ABC 转运蛋白的选择性调节奠定了框架，并为设计针对该蛋白家族的新型抗生素和其他治疗药物提供了合理途径。
