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Structural highlights
Function
[ACRZ_ECOLI] AcrA-AcrB-AcrZ-TolC is a drug efflux protein complex with a broad substrate specificity. This protein binds to AcrB and is required for efflux of some but not all substrates, suggesting it may influence the specificity of drug export.[1] [ACRA_ECOLI] AcrA-AcrB-AcrZ-TolC is a drug efflux protein complex with broad substrate specificity that uses the proton motive force to export substrates. This subunit may act as an adapter protein that links AcrB and TolC stably together. It is elongated in shape, being long enough to span the periplasm.[2] [ACRB_ECOLI] AcrAB is a drug efflux protein with a broad substrate specificity.[3] [4] [5] [TOLC_ECOLI] Outer membrane channel, which is required for the function of several efflux systems such as AcrAB-TolC, AcrEF-TolC, EmrAB-TolC and MacAB-TolC. These systems are involved in export of antibiotics and other toxic compounds from the cell. TolC is also involved in import of colicin E1 into the cells.[6] [7] [8] [9] [10]
Publication Abstract from PubMed
Bacterial efflux pumps confer multidrug resistance by transporting diverse antibiotics from the cell. In Gram-negative bacteria, some of these pumps form multi-protein assemblies that span the cell envelope. Here we report the near-atomic resolution cryoEM structures of the Escherichia coli AcrAB-TolC multidrug efflux pump in resting and drug transport states, revealing a quaternary structural switch that allosterically couples and synchronizes initial ligand binding with channel opening. Within the transport-activated state, the channel remains open even though the pump cycles through three distinct conformations. Collectively, our data provide a dynamic mechanism for the assembly and operation of the AcrAB-TolC pump.
An allosteric transport mechanism for the AcrAB-TolC Multidrug Efflux Pump.,Wang Z, Fan G, Hryc CF, Blaza JN, Serysheva II, Schmid MF, Chiu W, Luisi BF, Du D Elife. 2017 Mar 29;6. pii: e24905. doi: 10.7554/eLife.24905. PMID:28355133[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Hobbs EC, Yin X, Paul BJ, Astarita JL, Storz G. Conserved small protein associates with the multidrug efflux pump AcrB and differentially affects antibiotic resistance. Proc Natl Acad Sci U S A. 2012 Oct 9;109(41):16696-701. doi:, 10.1073/pnas.1210093109. Epub 2012 Sep 24. PMID:23010927 doi:https://dx.doi.org/10.1073/pnas.1210093109
- ↑ Zgurskaya HI, Nikaido H. AcrA is a highly asymmetric protein capable of spanning the periplasm. J Mol Biol. 1999 Jan 8;285(1):409-20. PMID:9878415 doi:https://dx.doi.org/10.1006/jmbi.1998.2313
- ↑ Murakami S, Nakashima R, Yamashita E, Matsumoto T, Yamaguchi A. Crystal structures of a multidrug transporter reveal a functionally rotating mechanism. Nature. 2006 Sep 14;443(7108):173-9. Epub 2006 Aug 16. PMID:16915237 doi:10.1038/nature05076
- ↑ Seeger MA, Schiefner A, Eicher T, Verrey F, Diederichs K, Pos KM. Structural asymmetry of AcrB trimer suggests a peristaltic pump mechanism. Science. 2006 Sep 1;313(5791):1295-8. PMID:16946072 doi:313/5791/1295
- ↑ Sennhauser G, Amstutz P, Briand C, Storchenegger O, Grutter MG. Drug export pathway of multidrug exporter AcrB revealed by DARPin inhibitors. PLoS Biol. 2007 Jan;5(1):e7. PMID:17194213 doi:10.1371/journal.pbio.0050007
- ↑ Morona R, Manning PA, Reeves P. Identification and characterization of the TolC protein, an outer membrane protein from Escherichia coli. J Bacteriol. 1983 Feb;153(2):693-9. PMID:6337123
- ↑ Kobayashi K, Tsukagoshi N, Aono R. Suppression of hypersensitivity of Escherichia coli acrB mutant to organic solvents by integrational activation of the acrEF operon with the IS1 or IS2 element. J Bacteriol. 2001 Apr;183(8):2646-53. PMID:11274125 doi:https://dx.doi.org/10.1128/JB.183.8.2646-2653.2001
- ↑ Touze T, Eswaran J, Bokma E, Koronakis E, Hughes C, Koronakis V. Interactions underlying assembly of the Escherichia coli AcrAB-TolC multidrug efflux system. Mol Microbiol. 2004 Jul;53(2):697-706. PMID:15228545 doi:https://dx.doi.org/10.1111/j.1365-2958.2004.04158.x
- ↑ Lin HT, Bavro VN, Barrera NP, Frankish HM, Velamakanni S, van Veen HW, Robinson CV, Borges-Walmsley MI, Walmsley AR. MacB ABC transporter is a dimer whose ATPase activity and macrolide-binding capacity are regulated by the membrane fusion protein MacA. J Biol Chem. 2009 Jan 9;284(2):1145-54. doi: 10.1074/jbc.M806964200. Epub 2008, Oct 27. PMID:18955484 doi:https://dx.doi.org/10.1074/jbc.M806964200
- ↑ Zakharov SD, Sharma O, Zhalnina M, Yamashita E, Cramer WA. Pathways of colicin import: utilization of BtuB, OmpF porin and the TolC drug-export protein. Biochem Soc Trans. 2012 Dec 1;40(6):1463-8. doi: 10.1042/BST20120211. PMID:23176499 doi:https://dx.doi.org/10.1042/BST20120211
- ↑ Wang Z, Fan G, Hryc CF, Blaza JN, Serysheva II, Schmid MF, Chiu W, Luisi BF, Du D. An allosteric transport mechanism for the AcrAB-TolC Multidrug Efflux Pump. Elife. 2017 Mar 29;6. pii: e24905. doi: 10.7554/eLife.24905. PMID:28355133 doi:https://dx.doi.org/10.7554/eLife.24905
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