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-Structure paper
タイトル | Substrate-bound and substrate-free outward-facing structures of a multidrug ABC exporter. |
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ジャーナル・号・ページ | Sci Adv, Vol. 8, Issue 4, Page eabg9215, Year 2022 |
掲載日 | 2022年1月28日 |
著者 | Vincent Chaptal / Veronica Zampieri / Benjamin Wiseman / Cédric Orelle / Juliette Martin / Kim-Anh Nguyen / Alexia Gobet / Margot Di Cesare / Sandrine Magnard / Waqas Javed / Jad Eid / Arnaud Kilburg / Marine Peuchmaur / Julien Marcoux / Luca Monticelli / Martin Hogbom / Guy Schoehn / Jean-Michel Jault / Ahcène Boumendjel / Pierre Falson / |
PubMed 要旨 | Multidrug ABC transporters translocate drugs across membranes by a mechanism for which the molecular features of drug release are so far unknown. Here, we resolved three ATP-Mg-bound outward-facing ...Multidrug ABC transporters translocate drugs across membranes by a mechanism for which the molecular features of drug release are so far unknown. Here, we resolved three ATP-Mg-bound outward-facing conformations of the (homodimeric) BmrA by x-ray crystallography and single-particle cryo-electron microscopy (EM) in detergent solution, one of them with rhodamine 6G (R6G), a substrate exported by BmrA when overexpressed in . Two R6G molecules bind to the drug-binding cavity at the level of the outer leaflet, between transmembrane (TM) helices 1-2 of one monomer and TM5'-6' of the other. They induce a rearrangement of TM1-2, highlighting a local flexibility that we confirmed by hydrogen/deuterium exchange and molecular dynamics simulations. In the absence of R6G, simulations show a fast postrelease occlusion of the cavity driven by hydrophobicity, while when present, R6G can move within the cavity, maintaining it open. |
リンク | Sci Adv / PubMed:35080979 / PubMed Central |
手法 | EM (単粒子) / X線回折 |
解像度 | 3.5 - 4.2 Å |
構造データ | EMDB-12170, PDB-7bg4: EMDB-13095, PDB-7ow8: EMDB-4749, PDB-6r81: PDB-6r72: |
化合物 | ChemComp-ATP: ChemComp-MG: ChemComp-RHQ: |
由来 |
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キーワード | TRANSPORT PROTEIN (運搬体タンパク質) / ABC transporter BmrA Multi-drug transporter / membrane protein (膜タンパク質) / ABC transporter / multidrug resistance (多剤耐性) / BmrA ABC transporter complex with ATP-Mg multidrug resistance |