Publikation:

The AcrB Efflux Pump : Conformational Cycling and Peristalsis Lead to Multidrug Resistance

Lade...
Vorschaubild

Dateien

Diederichs opus-119426.pdf
Diederichs opus-119426.pdfGröße: 11.35 MBDownloads: 1020

Datum

2008

Autor:innen

Seeger, Markus A.
Eicher, Thomas
Brandstätter, Lorenz
Schiefner, André
Verrey, François
Pos, Klaas M.

Herausgeber:innen

Kontakt

ISSN der Zeitschrift

Electronic ISSN

ISBN

Bibliografische Daten

Verlag

Schriftenreihe

Auflagebezeichnung

ArXiv-ID

Internationale Patentnummer

Angaben zur Forschungsförderung

Projekt

Open Access-Veröffentlichung
Open Access Green
Core Facility der Universität Konstanz

Gesperrt bis

Titel in einer weiteren Sprache

Publikationstyp
Zeitschriftenartikel
Publikationsstatus
Published

Erschienen in

Current Drug Targets. 2008, 9(9), pp. 729-749. ISSN 1389-4501. Available under: doi: 10.2174/138945008785747789

Zusammenfassung

Antimicrobial resistance of human pathogenic bacteria is an emerging problem for global public health. This resistance is often associated with the overproduction of membrane transport proteins that are capable to pump chemotherapeutics, antibiotics, detergents, dyes and organic solvents out of the cell. In Gram-negative bacteria such as Escherichia coli and Pseudomonas aeruginosa, tripartite multidrug efflux systems extrude a large variety of cytotoxic substances from the cell membrane directly into the medium bypassing the periplasm and the outer membrane. In E. coli, the tripartite efflux system AcrA/AcrB/TolC is the pump in charge of the efflux of multiple antibiotics, dyes, bile salts and detergents. The trimeric outer membrane factor (OMF) TolC forms a β-barrel pore in the outer membrane and exhibits a long periplasmic β-helical conduit. The periplasmic membrane fusion protein (MFP) AcrA serves as a linker between TolC and the trimeric resistance nodulation cell division (RND) pump AcrB, located in the inner membrane acting as a proton/drug antiporter. The newly elucidated asymmetric structure of trimeric AcrB reveals three different monomer conformations representing consecutive states in a transport cycle. The monomers show tunnels with occlusions at different sites leading from the lateral side through the periplasmic porter (pore) domains towards the funnel of the trimer and TolC. The structural changes create a hydrophobic pocket in one monomer, which is not present in the other two monomers. Minocyclin and doxorubicin, both AcrB substrates, specifically bind to this pocket substantiating its role as drug binding pocket. The energy transduction from the proton motive force into drug efflux includes proton binding in (and release from) the transmembrane part. The conformational changes observed within a triad of essential, titratable residues (Asp407/Asp408/Lys940) residing in the hydrophobic transmembrane domain appear to be transduced by transmembrane helix 8 and associated with the conformational changes seen in the periplasmic domain. From the asymmetric structure a possible peristaltic pump transport mechanism based on a functional rotation of the AcrB trimer has been postulated. The novel transport model merges Jardetzky's alternate access pump mechanism with the rotating site catalysis of F1Fo ATPase and suggests a working hypothesis for the transport mechanism of RND transporters in general.

Zusammenfassung in einer weiteren Sprache

Fachgebiet (DDC)
570 Biowissenschaften, Biologie

Schlagwörter

AcrB Efflux Pump, Antimicrobial resistance, human pathogenic bacteria, antibiotics, detergents

Konferenz

Rezension
undefined / . - undefined, undefined

Forschungsvorhaben

Organisationseinheiten

Zeitschriftenheft

Zugehörige Datensätze in KOPS

Zitieren

ISO 690SEEGER, Markus A., Kay DIEDERICHS, Thomas EICHER, Lorenz BRANDSTÄTTER, André SCHIEFNER, François VERREY, Klaas M. POS, 2008. The AcrB Efflux Pump : Conformational Cycling and Peristalsis Lead to Multidrug Resistance. In: Current Drug Targets. 2008, 9(9), pp. 729-749. ISSN 1389-4501. Available under: doi: 10.2174/138945008785747789
BibTex
@article{Seeger2008Efflu-1214,
  year={2008},
  doi={10.2174/138945008785747789},
  title={The AcrB Efflux Pump : Conformational Cycling and Peristalsis Lead to Multidrug Resistance},
  number={9},
  volume={9},
  issn={1389-4501},
  journal={Current Drug Targets},
  pages={729--749},
  author={Seeger, Markus A. and Diederichs, Kay and Eicher, Thomas and Brandstätter, Lorenz and Schiefner, André and Verrey, François and Pos, Klaas M.}
}
RDF
<rdf:RDF
    xmlns:dcterms="http://purl.org/dc/terms/"
    xmlns:dc="http://purl.org/dc/elements/1.1/"
    xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#"
    xmlns:bibo="http://purl.org/ontology/bibo/"
    xmlns:dspace="http://digital-repositories.org/ontologies/dspace/0.1.0#"
    xmlns:foaf="http://xmlns.com/foaf/0.1/"
    xmlns:void="http://rdfs.org/ns/void#"
    xmlns:xsd="http://www.w3.org/2001/XMLSchema#" > 
  <rdf:Description rdf:about="https://kops.uni-konstanz.de/server/rdf/resource/123456789/1214">
    <void:sparqlEndpoint rdf:resource="http://localhost/fuseki/dspace/sparql"/>
    <dc:contributor>Eicher, Thomas</dc:contributor>
    <dspace:isPartOfCollection rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/28"/>
    <dcterms:bibliographicCitation>Current Drug Targets ; 9 (2008), 9. - S. 729-749</dcterms:bibliographicCitation>
    <foaf:homepage rdf:resource="http://localhost:8080/"/>
    <dc:language>eng</dc:language>
    <dc:rights>terms-of-use</dc:rights>
    <dc:creator>Eicher, Thomas</dc:creator>
    <dcterms:isPartOf rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/28"/>
    <bibo:uri rdf:resource="http://kops.uni-konstanz.de/handle/123456789/1214"/>
    <dc:creator>Schiefner, André</dc:creator>
    <dcterms:rights rdf:resource="https://rightsstatements.org/page/InC/1.0/"/>
    <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2011-03-23T09:06:51Z</dc:date>
    <dc:creator>Verrey, François</dc:creator>
    <dcterms:available rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2011-03-23T09:06:51Z</dcterms:available>
    <dc:contributor>Seeger, Markus A.</dc:contributor>
    <dc:creator>Diederichs, Kay</dc:creator>
    <dc:contributor>Schiefner, André</dc:contributor>
    <dcterms:title>The AcrB Efflux Pump : Conformational Cycling and Peristalsis Lead to Multidrug Resistance</dcterms:title>
    <dc:creator>Brandstätter, Lorenz</dc:creator>
    <dc:contributor>Brandstätter, Lorenz</dc:contributor>
    <dc:creator>Pos, Klaas M.</dc:creator>
    <dcterms:abstract xml:lang="eng">Antimicrobial resistance of human pathogenic bacteria is an emerging problem for global public health. This resistance is often associated with the overproduction of membrane transport proteins that are capable to pump chemotherapeutics, antibiotics, detergents, dyes and organic solvents out of the cell. In Gram-negative bacteria such as Escherichia coli and Pseudomonas aeruginosa, tripartite multidrug efflux systems extrude a large variety of cytotoxic substances from the cell membrane directly into the medium bypassing the periplasm and the outer membrane. In E. coli, the tripartite efflux system AcrA/AcrB/TolC is the pump in charge of the efflux of multiple antibiotics, dyes, bile salts and detergents. The trimeric outer membrane factor (OMF) TolC forms a β-barrel pore in the outer membrane and exhibits a long periplasmic β-helical conduit. The periplasmic membrane fusion protein (MFP) AcrA serves as a linker between TolC and the trimeric resistance nodulation cell division (RND) pump AcrB, located in the inner membrane acting as a proton/drug antiporter. The newly elucidated asymmetric structure of trimeric AcrB reveals three different monomer conformations representing consecutive states in a transport cycle. The monomers show tunnels with occlusions at different sites leading from the lateral side through the periplasmic porter (pore) domains towards the funnel of the trimer and TolC. The structural changes create a hydrophobic pocket in one monomer, which is not present in the other two monomers. Minocyclin and doxorubicin, both AcrB substrates, specifically bind to this pocket substantiating its role as drug binding pocket. The energy transduction from the proton motive force into drug efflux includes proton binding in (and release from) the transmembrane part. The conformational changes observed within a triad of essential, titratable residues (Asp407/Asp408/Lys940) residing in the hydrophobic transmembrane domain appear to be transduced by transmembrane helix 8 and associated with the conformational changes seen in the periplasmic domain. From the asymmetric structure a possible peristaltic pump transport mechanism based on a functional rotation of the AcrB trimer has been postulated. The novel transport model merges Jardetzky's alternate access pump mechanism with the rotating site catalysis of F1Fo ATPase and suggests a working hypothesis for the transport mechanism of RND transporters in general.</dcterms:abstract>
    <dc:creator>Seeger, Markus A.</dc:creator>
    <dcterms:hasPart rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/1214/1/Diederichs%20opus-119426.pdf"/>
    <dc:contributor>Diederichs, Kay</dc:contributor>
    <dc:contributor>Verrey, François</dc:contributor>
    <dcterms:issued>2008</dcterms:issued>
    <dspace:hasBitstream rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/1214/1/Diederichs%20opus-119426.pdf"/>
    <dc:contributor>Pos, Klaas M.</dc:contributor>
  </rdf:Description>
</rdf:RDF>

Interner Vermerk

xmlui.Submission.submit.DescribeStep.inputForms.label.kops_note_fromSubmitter

Kontakt
URL der Originalveröffentl.

Prüfdatum der URL

Prüfungsdatum der Dissertation

Finanzierungsart

Kommentar zur Publikation

Allianzlizenz
Corresponding Authors der Uni Konstanz vorhanden
Internationale Co-Autor:innen
Universitätsbibliographie
Ja
Begutachtet
Diese Publikation teilen