tailieunhanh - Báo cáo khoa học: 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 exten-sively at the genetic and biochemical levels ever since. Pdr5, the most abun-dant 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. . | MINIREVIEW Multidrug efflux pumps Substrate selection in ATP-binding cassette multidrug efflux pumps - first come first served Robert Ernst1 z Petra Kueppers1 Jan Stindt1 Karl Kuchler2 and Lutz Schmitt1 1 Institute of Biochemistry Heinrich-Heine-University Duesseldorf Germany 2 Max F. Perutz Laboratories MedicalUniversity Vienna Austria Keywords ABCB1 ABC transporter ATP hydrolysis kinetic substrate selection ligand binding multidrug efflux multidrug resistance Pdr5 TAP transport mechanism Correspondence L. Schmitt Institute of Biochemistry Heinrich Heine University Duesseldorf Universitaetsstr. 1 40225 Duesseldorf Germany Fax 49 211 81 15310 Tel 49 211 81 10773 E-mail Present address Whitehead Institute for Biomedical Research Cambridge MA USA Received 22 July 2009 revised 1 October 2009 accepted 21 October 2009 doi 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. A brief history of multidrug resistance ATP-binding cassette transporters Multidrug resistance MDR strongly impacts the .