TAILIEUCHUNG - Báo cáo khoa học: Transmembrane helix 12 plays a pivotal role in coupling energy provision and drug binding in ABCB1

Describing the molecular details of the multidrug efflux process of ABCB1, in particular the interdomain communication associated with bioenergetic coupling, continues to prove difficult. A number of investigations to date have implicated transmembrane helix 12 (TM12) in mediating communica-tion between the transmembrane domains and nucleotide-binding domains (NBDs) of ABCB1. | Transmembrane helix 12 plays a pivotal role in coupling energy provision and drug binding in ABCB1 Emily Crowley1 Megan L. O Mara2 Ian D. Kerr3 and Richard Callaghan1 1 Nuffield Department of ClinicalLaboratory Sciences John Radcliffe Hospital University of Oxford UK 2 Molecular Dynamics Group Schoolof Chemistry and Molecular Biosciences University of Queensland Brisbane Australia 3 Schoolof BiomedicalSciences University of Nottingham Queen s MedicalCentre UK Keywords ABC transporter bioenergetic coupling drug resistance efflux pumps P-glycoprotein 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 5 May 2010 revised 2 July 2010 accepted 27 July 2010 doi Describing the molecular details of the multidrug efflux process of ABCB1 in particular the interdomain communication associated with bioenergetic coupling continues to prove difficult. A number of investigations to date have implicated transmembrane helix 12 TM12 in mediating communication between the transmembrane domains and nucleotide-binding domains NBDs of ABCB1. The present investigation further addressed the role of TM12 in ABCB1 by characterizing its topography during the multidrug efflux process with the use of cysteine-directed mutagenesis. Cysteines were introduced at various positions along TM12 and assessed for their ability to covalently bind thiol-reactive fluorescent probes with differing physiochemical properties. By analysing each isoform in the basal ATP-bound and posthydrolytic states it was possible to determine how the local environment of TM12 alters during the catalytic cycle. Labelling with hydrophobic CM and zwitterionic BM was extensive throughout the helix in the basal prehydrolytic and posthydrolytic states suggesting that TM12 is in a predominantly hydrophobic environment. .

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