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Received for publication April 14, 2004.
Revised August 5, 2004.
Accepted for publication August 5, 2004.
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 MALDI-TOF mass-spectrometry. In the non-energized state labeling occurred in the 
-helical transmembrane segments 3, 5 and 6 of the membrane-spanning domain. Upon nucleotide-binding the accessibility of TM5 for substrates increased, while 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.
Key words:
MDR/p-Glycoprotein, Structure-activity relationships and modeling, Mass Spectroscopy, Antibiotic resistance, Resistance
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