Multidrug Resistance Mediated by a Bacterial Homolog of the Human Multidrug Transporter MDR1

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 93; no. 20; pp. 10668 - 10672
• Main Authors: Van Veen, Hendrik W., Venema, Koen, Bolhuis, Henk, Oussenko, Irina, Kok, Jan, Poolman, Bert, Arnold J. M. Driessen, Konings, Wil N.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 01.10.1996; National Acad Sciences
• Subjects: Amino Acid Sequence; ATP binding cassette transporters; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Bacterial Proteins; Biochemistry; Cancer; Cell lines; DNA; Drug Resistance, Microbial; Drug Resistance, Multiple; Escherichia coli; Genes, Bacterial; Genes, MDR; Humans; Lactobacillus - drug effects; Lactobacillus - genetics; Lactococcus lactis; Membrane Proteins - physiology; Molecular Sequence Data; Multidrug Resistance-Associated Proteins; Multiple drug resistance; P branes; Plasmids; Proteins; Protons; Sequence Alignment; Sequence Homology, Amino Acid
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.93.20.10668

Resistance of Lactococcus lactis to cytotoxic compounds shares features with the multidrug resistance phenotype of mammalian tumor cells. Here, we report the gene cloning and functional characterization in Escherichia coli of LmrA, a lactococcal structural and functional homolog of the human multidrug resistance P-glycoprotein MDR1. LmrA is a 590-aa polypeptide that has a putative topology of six $\alpha $-helical transmembrane segments in the N-terminal hydro-phobic domain, followed by a hydrophilic domain containing the ATP-binding site. LmrA is similar to each of the two halves of MDR1 and may function as a homodimer. The sequence conservation between LmrA and MDR1 includes particular regions in the transmembrane domains and connecting loops, which, in MDR1 and the MDR1 homologs in other mammalian species, have been implicated as determinants of drug recognition and binding. LmrA and MDR1 extrude a similar spectrum of amphiphilic cationic compounds, and the activity of both systems is reversed by reserpine and verapamil. As LmrA can be functionally expressed in E. coli, it offers a useful prokaryotic model for future studies on the molecular mechanism of MDR1-like multidrug transporters.