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Sequential mechanism of assembly of multidrug efflux pump AcrAB-TolC.
Chem Biol. 2011 Apr 22; 18(4):454-63.CB

Abstract

Multidrug efflux pumps adversely affect both the clinical effectiveness of existing antibiotics and the discovery process to find new ones. In this study, we reconstituted and characterized by surface plasmon resonance the assembly of AcrAB-TolC, the archetypal multidrug efflux pump from Escherichia coli. We report that the periplasmic AcrA and the outer membrane channel TolC assemble high-affinity complexes with AcrB transporter independently from each other. Antibiotic novobiocin and MC-207,110 inhibitor bind to the immobilized AcrB but do not affect interactions between components of the complex. In contrast, DARPin inhibits interactions between AcrA and AcrB. Mutational opening of TolC channel decreases stability of interactions and promotes disassembly of the complex. The conformation of the membrane proximal domain of AcrA is critical for the formation of AcrAB-TolC and could be targeted for the development of new inhibitors.

Authors+Show Affiliations

Department of Chemistry and Biochemistry, Stephenson Life Science Research Center, University of Oklahoma, Norman, OK 73019, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

21513882

Citation

Tikhonova, Elena B., et al. "Sequential Mechanism of Assembly of Multidrug Efflux Pump AcrAB-TolC." Chemistry & Biology, vol. 18, no. 4, 2011, pp. 454-63.
Tikhonova EB, Yamada Y, Zgurskaya HI. Sequential mechanism of assembly of multidrug efflux pump AcrAB-TolC. Chem Biol. 2011;18(4):454-63.
Tikhonova, E. B., Yamada, Y., & Zgurskaya, H. I. (2011). Sequential mechanism of assembly of multidrug efflux pump AcrAB-TolC. Chemistry & Biology, 18(4), 454-63. https://doi.org/10.1016/j.chembiol.2011.02.011
Tikhonova EB, Yamada Y, Zgurskaya HI. Sequential Mechanism of Assembly of Multidrug Efflux Pump AcrAB-TolC. Chem Biol. 2011 Apr 22;18(4):454-63. PubMed PMID: 21513882.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sequential mechanism of assembly of multidrug efflux pump AcrAB-TolC. AU - Tikhonova,Elena B, AU - Yamada,Yoichi, AU - Zgurskaya,Helen I, PY - 2011/01/05/received PY - 2011/02/16/revised PY - 2011/02/28/accepted PY - 2011/4/26/entrez PY - 2011/4/26/pubmed PY - 2011/9/7/medline SP - 454 EP - 63 JF - Chemistry & biology JO - Chem. Biol. VL - 18 IS - 4 N2 - Multidrug efflux pumps adversely affect both the clinical effectiveness of existing antibiotics and the discovery process to find new ones. In this study, we reconstituted and characterized by surface plasmon resonance the assembly of AcrAB-TolC, the archetypal multidrug efflux pump from Escherichia coli. We report that the periplasmic AcrA and the outer membrane channel TolC assemble high-affinity complexes with AcrB transporter independently from each other. Antibiotic novobiocin and MC-207,110 inhibitor bind to the immobilized AcrB but do not affect interactions between components of the complex. In contrast, DARPin inhibits interactions between AcrA and AcrB. Mutational opening of TolC channel decreases stability of interactions and promotes disassembly of the complex. The conformation of the membrane proximal domain of AcrA is critical for the formation of AcrAB-TolC and could be targeted for the development of new inhibitors. SN - 1879-1301 UR - https://www.unboundmedicine.com/medline/citation/21513882/Sequential_mechanism_of_assembly_of_multidrug_efflux_pump_AcrAB_TolC_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1074-5521(11)00090-1 DB - PRIME DP - Unbound Medicine ER -