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Drug export pathway of multidrug exporter AcrB revealed by DARPin inhibitors


Sennhauser, G; Amstutz, P; Briand, C; Storchenegger, O; Grütter, M G (2007). Drug export pathway of multidrug exporter AcrB revealed by DARPin inhibitors. PLoS Biology, 5(1):e7.

Abstract

The multidrug exporter AcrB is the inner membrane component of the AcrAB-TolC drug efflux system in Escherichia coli and is responsible for the resistance of this organism to a wide range of drugs. Here we describe the crystal structure of the trimeric AcrB in complex with a designed ankyrin-repeat protein (DARPin) inhibitor at 2.5 A resolution. The three subunits of AcrB are locked in different conformations revealing distinct channels in each subunit. There seems to be remote conformational coupling between the channel access, exit, and the putative proton-translocation site, explaining how the proton motive force is used for drug export. Thus our structure suggests a transport pathway not through the central pore but through the identified channels in the individual subunits, which greatly advances our understanding of the multidrug export mechanism.

The multidrug exporter AcrB is the inner membrane component of the AcrAB-TolC drug efflux system in Escherichia coli and is responsible for the resistance of this organism to a wide range of drugs. Here we describe the crystal structure of the trimeric AcrB in complex with a designed ankyrin-repeat protein (DARPin) inhibitor at 2.5 A resolution. The three subunits of AcrB are locked in different conformations revealing distinct channels in each subunit. There seems to be remote conformational coupling between the channel access, exit, and the putative proton-translocation site, explaining how the proton motive force is used for drug export. Thus our structure suggests a transport pathway not through the central pore but through the identified channels in the individual subunits, which greatly advances our understanding of the multidrug export mechanism.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:January 2007
Deposited On:29 Jul 2008 09:33
Last Modified:09 Aug 2016 10:47
Publisher:Public Library of Science (PLoS)
ISSN:1544-9173
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:10.1371/journal.pbio.0050007
PubMed ID:17194213
Permanent URL: http://doi.org/10.5167/uzh-2752

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