Structure of MsbA from E-coli: A homolog of the multidrug resistance ATP binding cassette (ABC) transporters

Multidrug resistance (MDR) is a serious medical problem and presents a majo r challenge to the treatment of disease and the development of novel therap eutics. ABC transporters that are associated with multidrug resistance (MDR -ABC transporters) translocate hydrophobic drugs and lipids from the inner to the outer leaflet of the cell membrane. To better elucidate the structur al basis for the "flip-flop" mechanism of substrate movement across the lip id bilayer, we have determined the structure of the lipid flippase MsbA fro m Escherichia coli by x-ray crystallography to a resolution of 4.5 angstrom s. MsbA is organized as a homodimer with each subunit containing six transm embrane alpha -helices and a nucleotide-binding domain. The asymmetric dist ribution of charged residues lining a central chamber suggests a general me chanism for the translocation of substrate by MsbA and other MDR-ABC transp orters. The structure of MsbA can serve as a model for the MDR-ABC transpor ters that confer multidrug resistance to cancer cells and infectious microo rganisms.