Multidrug resistance (MDR) presents a significant challenge to the treatment of disease and the development of novel therapeutics. The x‐ray structures of the multidrug resistance ABC (MDR‐ABC) transporter homolog MsbA reveal the molecular structural basis of lipid/drug transport. MsbA is organized as a dimer with each subunit containing six transmembrane ƒÑ‐helices and a nucleotide‐binding domain or ATP binding Cassette (ABC). The asymmetric distribution of charged residues lining a central chamber in the cell membrane suggests a general mechanism for the translocation of hydrophobic substrate by MsbA and, by sequence homology, to other MDR‐ABC transporters. The open and closed conformations of MsbA reveal the structural changes that are possible by ABC exporters. The recent structure of the MsbA complexed with magnesium, ADP, inorganic vanadate, and lipopolysaccharide (Ra LPS) reveals a model involving a rigid‐body torque of the two transmembrane domains during ATP hydrolysis. This model suggests a mechanism by which the ABC communicates with the transmembrane domain. We propose a lipid ¡§flip‐flop¡¨ mechanism in which the sugar groups are sequestered in the chamber while the hydrophobic tails are dragged through the lipid bilayer.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.