7M33

The structure of Bacillus subtilis BmrCD in the inward-facing conformation bound to Hoechst-33342 and ATP

7M33 の概要

• エントリーDOI: 10.2210/pdb7m33/pdb
• EMDBエントリー: 23641
• 分子名称: Probable multidrug resistance ABC transporter ATP-binding/permease protein YheI, Probable multidrug resistance ABC transporter ATP-binding/permease protein YheH, ADENOSINE-5'-TRIPHOSPHATE, ... (4 entities in total)
• 機能のキーワード: abc transporter, multi-drug efflux transporter, abc exporter, transport protein
• 由来する生物種: Bacillus subtilis subsp. subtilis str. 168; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 146892.32

構造登録者

Thaker, T.M.,Tomasiak, T.M. (登録日: 2021-03-18, 公開日: 2022-01-05, 最終更新日: 2024-05-29)

主引用文献

Thaker, T.M.,Mishra, S.,Zhou, W.,Mohan, M.,Tang, Q.,Faraldo-Gomez, J.D.,Mchaourab, H.S.,Tomasiak, T.M.
Asymmetric drug binding in an ATP-loaded inward-facing state of an ABC transporter.
Nat.Chem.Biol., 18:226-235, 2022

PubMed Abstract: Substrate efflux by ATP-binding cassette (ABC) transporters, which play a major role in multidrug resistance, entails the ATP-powered interconversion between transporter intermediates. Despite recent progress in structure elucidation, a number of intermediates have yet to be visualized and mechanistically interpreted. Here, we combine cryogenic-electron microscopy (cryo-EM), double electron-electron resonance spectroscopy and molecular dynamics simulations to profile a previously unobserved intermediate of BmrCD, a heterodimeric multidrug ABC exporter from Bacillus subtilis. In our cryo-EM structure, ATP-bound BmrCD adopts an inward-facing architecture featuring two molecules of the substrate Hoechst-33342 in a striking asymmetric head-to-tail arrangement. Deletion of the extracellular domain capping the substrate-binding chamber or mutation of Hoechst-coordinating residues abrogates cooperative stimulation of ATP hydrolysis. Together, our findings support a mechanistic role for symmetry mismatch between the nucleotide binding and the transmembrane domains in the conformational cycle of ABC transporters and is of notable importance for rational design of molecules for targeted ABC transporter inhibition.

PubMed: 34931066
DOI: 10.1038/s41589-021-00936-x

実験手法

ELECTRON MICROSCOPY (3.55 Å)