TAILIEUCHUNG - Báo cáo khoa học: Is ATP binding responsible for initiating drug translocation by the multidrug transporter ABCG2?

ABCG2 confers resistance to cancer cells by mediating the ATP-dependent outward efflux of chemotherapeutic compounds. Recent studies have indi-cated that the protein contains a number of interconnected drug binding sites. The present investigation examines the coupling of drug binding to ATP hydrolysis. | ễFEBS Journal Is ATP binding responsible for initiating drug translocation by the multidrug transporter ABCG2 Christopher A. McDevitt1 Emily Crowley1 Gemma Hobbs1 Kate J. Starr2 Ian D. Kerr2 and Richard Callaghan1 1 Nuffield Department of ClinicalLaboratory Sciences John Radcliffe Hospital University of Oxford UK 2 Centre for Biochemistry and CellBiology Schoolof BiomedicalSciences University of Nottingham UK Keywords ABC transporter chemotherapy membrane protein multidrug-resistance power-stroke Correspondence R. Callaghan Nuffield Department of Clinical Laboratory Sciences John Radcliffe Hospital University of Oxford Oxford OX3 9DU UK Fax 44 1865 221 834 Tel 44 1865 221 110 E-mail Received 28 May 2008 revised 24 June 2008 accepted 27 June 2008 doi ABCG2 confers resistance to cancer cells by mediating the ATP-dependent outward efflux of chemotherapeutic compounds. Recent studies have indicated that the protein contains a number of interconnected drug binding sites. The present investigation examines the coupling of drug binding to ATP hydrolysis. Initial drug binding to the protein requires a high-affinity interaction with the drug binding site followed by transition and reorientation to the low-affinity state to enable dissociation at the extracellular face. 3H Daunomycin binding to the ABCG2R482G isoform was examined in the nucleotide-bound and post-hydrolytic conformations. Binding of 3H daunomycin was displaced by ATP analogues indicating transition to a low-affinity conformation prior to hydrolysis. The low-affinity state was observed to be retained immediately post-hydrolysis. Therefore the dissociation of phosphate and or ADP is likely to be responsible for resetting of the transporter. The data indicate that like ABCB1 and ABCC1 the power stroke for translocation in ABCG2R482G is the binding of nucleotide. Resistance to chemotherapy presents a continuing and significant obstacle in the .

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