ArticlePLoS computational biology2010
Functional rotation of the transporter AcrB: insights into drug extrusion from simulations.
Article in PLoS computational biology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed.
- Structural insights into a substrate translocation pathway revealed by the RND efflux pump complex MexJK fromScience advances · 2026Article
- Substrate Specificity Checkpoints of the Multidrug Efflux Pump MexF fromACS infectious diseases · 2026Article
- Computer Simulations of Multidrug Efflux Pumps of the Resistance-Nodulation-Cell Division Superfamily.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Advances in methods and concepts provide new insight into antibiotic fluxes across the bacterial membrane.Communications biology · 2024Article
- Structural and functional diversity of Resistance-Nodulation-Division (RND) efflux pump transporters with implications for antimicrobial resistance.Microbiology and molecular biology reviews : MMBR · 2024Review
- RND multidrug efflux transporters: similar appearances, diverse actions.Journal of bacteriology · 2024Article
- Article
- Tripartite efflux pumps of the RND superfamily: what did we learn from computational studies?Microbiology (Reading, England) · 2023Review
- Common recognition topology of mex transporters ofFrontiers in pharmacology · 2022Article
- Structure and function relationship of OqxB efflux pump from Klebsiella pneumoniae.Nature communications · 2021Article
- Insight into the AcrAB-TolC Complex Assembly Process Learned from Competition Studies.Antibiotics (Basel, Switzerland) · 2021Article
- MexAB-OprM Efflux Pump Interaction with the Peptidoglycan ofInternational journal of molecular sciences · 2021Article
- Antibiotic export by MexB multidrug efflux transporter is allosterically controlled by a MexA-OprM chaperone-like complex.Nature communications · 2020Article
- Probing the Dynamics of AcrB Through Disulfide Bond Formation.ACS omega · 2020Article
- Article
- Chlorpromazine and Amitriptyline Are Substrates and Inhibitors of the AcrB Multidrug Efflux Pump.mBio · 2020Article
- Molecular Interactions of Carbapenem Antibiotics with the Multidrug Efflux Transporter AcrB ofInternational journal of molecular sciences · 2020Article
- Article
- Molecular Interactions of Cephalosporins with the Deep Binding Pocket of the RND Transporter AcrB.The journal of physical chemistry. B · 2019Article
- Crystal structures of multidrug efflux pump MexB bound with high-molecular-mass compounds.Scientific reports · 2019Article
Corrections and comments
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Authors and funding
5 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The tripartite complex AcrAB-TolC is the major efflux system in Escherichia coli. It extrudes a wide spectrum of noxious compounds out of the bacterium, including many antibiotics. Its active part, the homotrimeric transporter AcrB, is responsible for the selective binding of substrates and energy transduction. Based on available crystal structures and biochemical data, the transport of substrates by AcrB has been proposed to take place via a functional rotation, in which each monomer assumes a particular conformation. However, there is no molecular-level description of the conformational changes associated with the rotation and their connection to drug extrusion. To obtain insights thereon, we have performed extensive targeted molecular dynamics simulations mimicking the functional rotation of AcrB containing doxorubicin, one of the two substrates that were co-crystallized so far. The simulations, including almost half a million atoms, have been used to test several hypotheses concerning the structure-dynamics-function relationship of this transporter. Our results indicate that, upon induction of conformational changes, the substrate detaches from the binding pocket and approaches the gate to the central funnel. Furthermore, we provide strong evidence for the proposed peristaltic transport involving a zipper-like closure of the binding pocket, responsible for the displacement of the drug. A concerted opening of the channel between the binding pocket and the gate further favors the displacement of the drug. This microscopically well-funded information allows one to identify the role of specific amino acids during the transitions and to shed light on the functioning of AcrB.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.