Multidrug efflux pumps: substrate selection in ATP-binding cassette multidrug efflux pumps--first come, first served?
Multidrug resistance is a major challenge in the therapy of cancer and pathogenic fungal infections. More than three decades ago, P-glycoprotein was the first identified multidrug transporter. It has been studied extensively at the genetic and biochemical levels ever since. Pdr5, the most abundant ATP-binding cassette transporter in Saccharomyces cerevisiae, is highly homologous to azole-resistance-mediating multidrug transporters in fungal pathogens, and a focus of clinical drug resistance research. Despite functional equivalences, P-glycoprotein and Pdr5 exhibit striking differences in their architecture and mechanisms. In this minireview, we discuss the mechanisms of substrate selection and multidrug transport by comparing the fraternal twins P-glycoprotein and Pdr5. We propose that substrate selection in eukaryotic multidrug ATP-binding cassette transporters is not solely determined by structural features of the transmembrane domains but also by their dynamic behavior.
Ernst
Robert
R
Institute of Biochemistry, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany.
Kueppers
Petra
P
Stindt
Jan
J
Kuchler
Karl
K
Schmitt
Lutz
L
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000235:genetics / Q000502:physiology; D007700:Kinetics; D008954:Models, Biological; D017434:Protein Structure, Tertiary / Q000502:physiology; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000502:physiology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; C092438:PDR5 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D000251:Adenosine Triphosphatases