Structure of MsbA from Vibrio cholera: a multidrug resistance ABC transporter homolog in a closed conformation.
The spread of multidrug resistance (MDR) is a world health crisis that presents a significant challenge to the treatment of cancer and infection. MDR can be caused by a group of ABC (MDR-ABC) transporters that move hydrophobic drug molecules and lipids across the cell membrane. To gain insight into the conformational changes these transporters undergo when flipping hydrophobic substrates across the lipid bilayer, we have determined the structure of the lipid flippase MsbA from Vibrio cholera (VC-MsbA) to 3.8A. Structural comparison of VC-MsbA to MsbA from Escherichia coli reveals that the transporters share a structurally conserved core of transmembrane alpha-helices, but differ in the relative orientations of their nucleotide-binding domains (NBD). The transmembrane domain of VC-MsbA is captured in a closed conformation and the structure supports a "power stroke" model of transporter dynamics where opposing NBDs associate upon ATP binding. The separation of the alpha and beta domains of the NBD suggests the possibility that their association could make them competent to bind ATP and gives further insight into the structural basis for catalytic regulation.
Chang
Geoffrey
G
Department of Molecular Biology, CB-105, The Scripps Research Institute, La Jolla, CA 92037, USA. gchang@scripps.edu
D018528:ATP-Binding Cassette Transporters / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D024901:Drug Resistance, Multiple, Bacterial; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014734:Vibrio cholerae / Q000737:chemistry* / Q000235:genetics
D018528:ATP-Binding Cassette Transporters; D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; C079726:MsbA protein, Bacteria; D011994:Recombinant Proteins