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Structure of Multidrug Transporters
Author(s) -
Chang Geoffrey A
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a888
Subject(s) - atp binding cassette transporter , transmembrane domain , lipid bilayer , chemistry , transmembrane protein , multiple drug resistance , cyclic nucleotide binding domain , protein subunit , atp hydrolysis , biochemistry , homology modeling , transporter , biophysics , biology , nucleotide , enzyme , membrane , gene , atpase , receptor , antibiotics
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.