研究人员表示，ABC（ATP-binding cassette）转运体将ATP水解与底物运输结合在一起，从而跨越生物膜。尽管许多转运体是有前途的药物靶标，但它们被小分子抑制剂调控的机制在很大程度上仍是未知的。有趣的是，MsbA转运体的两个第一代抑制剂TBT1和G247对ATP水解产生了相反的影响。
通过使用单粒子冷冻电镜和功能检测，研究人员表明TBT1和G247在MsbA跨膜结构域中结合了相邻但独立的口袋。两个TBT1分子不对称地占据了底物结合位点，导致核苷酸结合结构域（NBD）之间的距离减少，形成一个塌陷的朝内构象。相反，两个G247分子对称地增加了MsbA宽内向开放状态下的NBD距离。这些MsbA抑制剂的不同作用机制为ABC转运体的药理学提供了重要的见解。
附：英文原文
Title: Distinct allosteric mechanisms of first-generation MsbA inhibitors
Author: Franois A. Thélot, Wenyi Zhang, KangKang Song, Chen Xu, Jing Huang, Maofu Liao
Issue&Volume: 2021-10-29
Abstract: ATP-binding cassette (ABC) transporters couple ATP hydrolysis to substrate transport across biological membranes. Although many are promising drug targets, their mechanisms of modulation by small molecule inhibitors remain largely unknown. Intriguingly, two first-generation inhibitors of the MsbA transporter, TBT1 and G247, induce opposite effects on ATP hydrolysis. Using single-particle cryo-electron microscopy and functional assays, we show that TBT1 and G247 bind adjacent yet separate pockets in the MsbA transmembrane domains. Two TBT1 molecules asymmetrically occupy the substrate binding site, leading to a collapsed inward-facing conformation with decreased distance between the nucleotide-binding domains (NBDs). In contrast, two G247 molecules symmetrically increases NBD distance in a wide inward-open state of MsbA. The divergent mechanisms of action of these MsbA inhibitors provide important insights into ABC transporter pharmacology.
DOI: abi9009
Source: https://www.science.org/doi/10.1126/science.abi9009