7MET

A. baumannii MsbA in complex with TBT1 decoupler

7MET の概要

• エントリーDOI: 10.2210/pdb7met/pdb
• EMDBエントリー: 23803
• 分子名称: ATP-dependent lipid A-core flippase, 2-(4-chlorobenzamido)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylic acid (2 entities in total)
• 機能のキーワード: membrane protein
• 由来する生物種: Acinetobacter baumannii
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 136188.99

構造登録者

Thelot, F.,Liao, M. (登録日: 2021-04-07, 公開日: 2021-10-06, 最終更新日: 2024-05-29)

主引用文献

Thelot, F.A.,Zhang, W.,Song, K.,Xu, C.,Huang, J.,Liao, M.
Distinct allosteric mechanisms of first-generation MsbA inhibitors.
Science, 374:580-585, 2021

PubMed Abstract: ATP-binding cassette (ABC) transporters couple adenosine 5′-triphosphate (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. Two first-generation inhibitors of the MsbA transporter, tetrahydrobenzothiophene 1 (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, which leads to a collapsed inward-facing conformation with decreased distance between the nucleotide-binding domains (NBDs). By contrast, two G247 molecules symmetrically increase 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.

PubMed: 34554829
DOI: 10.1126/science.abi9009

実験手法

ELECTRON MICROSCOPY (3.97 Å)