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First published on August 10, 2004; DOI: 10.1124/mol.104.001420

0026-895X/04/6605-1169-1179$20.00
Mol Pharmacol 66:1169-1179, 2004

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A Three-Dimensional Model for the Substrate Binding Domain of the Multidrug ATP Binding Cassette Transporter LmrA

Gerhard F. Ecker, Karin Pleban, Stephan Kopp, Edina Csaszar, Gerrit J. Poelarends1, Monique Putman, Dominik Kaiser, Wil N. Konings, and Peter Chiba

Institute of Medical Chemistry (S.K., P.C.), Medical University of Vienna, Department of Pharmaceutical Chemistry (G.F.E., K.P., D.K.), and the Mass Spectrometry Unit (E.C.), University of Vienna, Vienna, Austria; and Department of Microbiology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, the Netherlands (G.J.P., M.P., W.N.K.)

Multidrug resistance presents a major obstacle to the treatment of infectious diseases and cancer. LmrA, a bacterial ATP-dependent multidrug transporter, mediates efflux of hydrophobic cationic substrates, including antibiotics. The substrate-binding domain of LmrA was identified by using photo-affinity ligands, proteolytic degradation of LmrA, and identification of ligand-modified peptide fragments with matrix-assisted laser desorption ionization/time of flight mass spectrometry. In the nonenergized state, labeling occurred in the {alpha}-helical transmembrane segments (TM) 3, 5 and 6 of the membrane-spanning domain. Upon nucleotide binding, the accessibility of TM5 for substrates increased, whereas that of TM6 decreased. Inverse changes were observed upon ATP-hydrolysis. An atomic-detail model of dimeric LmrA was generated based on the template structure of the homologous transporter MsbA from Vibrio cholerae, allowing a three-dimensional visualization of the substrate-binding domain. Labeling of TM3 of one monomer occurred in a predicted area of contact with TM5 or TM6 of the opposite monomer, indicating substrate-binding at the monomer/monomer interface. Inverse changes in the reactivity of TM segments 5 and 6 suggest that substrate binding and release involves a repositioning of these helices during the catalytic cycle.

Received April 14, 2004; accepted August 5, 2004

Address correspondence to: Peter Chiba, Institute of Medical Chemistry, Medical University of Vienna, Waehringerstrasse 10, A-1090 Vienna, Austria. E-mail: peter.chiba{at}univie.ac.at




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