A three-dimensional model for the substrate binding domain of the multidrug ATP binding cassette transporter LmrA. Mol Pharmacol 66:1169–1179

Multidrug resistance presents a major obstacle to the treatment of infectious diseases and cancer. LmrA, a bacterial ATP-de-pendent multidrug transporter, mediates efflux of hydrophobic cationic substrates, including antibiotics. The substrate-bind-ing domain of LmrA was identified by using photo-affinity li-gands, 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 -helical trans-membrane segments (TM) 3, 5 and 6 of the membrane-span-ning domain. Upon nucleotide binding, the accessibility of TM5 for substrates increased, whereas that of TM6 decreased. In-verse changes were observed upon ATP-hydrolysis. An atom-ic-detail model of dimeric LmrA was generated based on th