Binding and Transport of Carboxylated Drugs by the Multidrug Transporter AcrB.
crystallography
drug transport
efflux
membrane protein
molecular modeling
Journal
Journal of molecular biology
ISSN: 1089-8638
Titre abrégé: J Mol Biol
Pays: Netherlands
ID NLM: 2985088R
Informations de publication
Date de publication:
14 02 2020
14 02 2020
Historique:
received:
18
10
2019
revised:
11
12
2019
accepted:
12
12
2019
pubmed:
28
12
2019
medline:
18
8
2020
entrez:
28
12
2019
Statut:
ppublish
Résumé
AcrAB(Z)-TolC is the main drug efflux transporter complex in Escherichia coli. The extrusion of various toxic compounds depends on several drug binding sites within the trimeric AcrB transporter. Membrane-localized carboxylated substrates, such as fusidic acid and hydrophobic β-lactams, access the pump via a groove between the transmembrane helices TM1 and TM2. In this article, the transport route from the initial TM1/TM2 groove binding site toward the deep binding pocket located in the periplasmic part has been addressed via molecular modeling studies followed by functional and structural characterization of several AcrB variants. We propose that membrane-embedded drugs bind initially to the TM1/TM2 groove, are oriented by the AcrB PN2 subdomain, and are subsequently transported via a PN2/PC1 interface pathway directly toward the deep binding pocket. Our work emphasizes the exploitation of multiple transport pathways by AcrB tuned to substrate physicochemical properties related to the polyspecificity of the pump.
Identifiants
pubmed: 31881208
pii: S0022-2836(19)30734-X
doi: 10.1016/j.jmb.2019.12.025
pmc: PMC7071731
mid: NIHMS1549351
pii:
doi:
Substances chimiques
AcrB protein, E coli
0
Escherichia coli Proteins
0
Multidrug Resistance-Associated Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
861-877Subventions
Organisme : NIAID NIH HHS
ID : R01 AI136799
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier Ltd. All rights reserved.
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