ArticleScientific reports2015
Stepwise substrate translocation mechanism revealed by free energy calculations of doxorubicin in the multidrug transporter AcrB.
Article in Scientific reports, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 19 citations in OpenAlex.
- RND efflux pump inhibitor-like natural products as antibiotic adjuvants against multidrug-resistant gram-negative bacteria: a graded-evidence review.Frontiers in microbiology · 2026Review
- Tripartite efflux pumps of the RND superfamily: what did we learn from computational studies?Microbiology (Reading, England) · 2023Review
- Functionally distinct mutations within AcrB underpin antibiotic resistance in different lifestyles.npj antimicrobials and resistance · 2023Article
- Article
- Binding and Transport of Carboxylated Drugs by the Multidrug Transporter AcrB.Journal of molecular biology · 2020Article
- Mapping the Dynamic Functions and Structural Features of AcrB Efflux Pump Transporter Using Accelerated Molecular Dynamics Simulations.Scientific reports · 2018Article
- Energetics and conformational pathways of functional rotation in the multidrug transporter AcrB.eLife · 2018Article
- Molecular Determinants of the Promiscuity of MexB and MexY Multidrug Transporters ofFrontiers in microbiology · 2018Article
- Molecular Rationale behind the Differential Substrate Specificity of Bacterial RND Multi-Drug Transporters.Scientific reports · 2017Article
- Evidence of a Substrate-Discriminating Entrance Channel in the Lower Porter Domain of the Multidrug Resistance Efflux Pump AcrB.Antimicrobial agents and chemotherapy · 2016Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
AcrB is the inner membrane transporter of the tripartite multidrug efflux pump AcrAB-TolC in E. coli, which poses a major obstacle to the treatment of bacterial infections. X-ray structures have identified two types of substrate-binding pockets in the porter domains of AcrB trimer: the proximal binding pocket (PBP) and the distal binding pocket (DBP), and suggest a functional rotating mechanism in which each protomer cycles consecutively through three distinct conformational states (access, binding and extrusion). However, the details of substrate binding and translocation between the binding pockets remain elusive. In this work, we performed atomic simulations to obtain the free energy profile of the translocation of an antibiotic drug doxorubicin (DOX) inside AcrB. Our simulation indicates that DOX binds at the PBP and DBP with comparable affinities in the binding state protomer, and overcomes a 3 kcal/mol energy barrier to transit between them. Obvious conformational changes including closing of the PC1/PC2 cleft and shrinking of the DBP were observed upon DOX binding in the PBP, resulting in an intermediate state between the access and binding states. Taken together, the simulation results reveal a detailed stepwise substrate binding and translocation process in the framework of functional rotating mechanism.
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