Location of contact residues in pharmacologically distinct drug binding sites on P-glycoprotein

Mittra, Rituparna and Pavy, Megan and Subramanian, Nanditha and George, Anthony M. and O'Mara, Megan L. and Kerr, Ian D. and Callaghan, Richard (2017) Location of contact residues in pharmacologically distinct drug binding sites on P-glycoprotein. Biochemical Pharmacology, 123 . pp. 19-28. ISSN 0006-2952

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Abstract

The multidrug resistance P-glycoprotein (P-gp) is characterised by the ability to bind and/or transport an astonishing array of drugs. This poly-specificity is imparted by at least four pharmacologically distinct binding sites within the transmembrane domain. Whether or not these sites are spatially distinct has remained unclear. Biochemical and structural investigations have implicated a central cavity as the likely location for the binding sites. In the present investigation, a number of contact residues that are involved in drug binding were identified through biochemical assays using purified, reconstituted P-gp. Drugs were selected to represent each of the four pharmacologically distinct sites. Contact residues important in rhodamine123 binding were identified in the central cavity of P-gp. However, contact residues for the binding of vinblastine, paclitaxel and nicardipine were located at the lipid-protein interface rather than the central cavity. A key residue (F978) within the central cavity is believed to be involved in coupling drug binding to nucleotide hydrolysis. Data observed in this investigation suggest the presence of spatially distinct drug binding sites connecting through to a single translocation pore in the central cavity.

Item Type: Article
Keywords: P-glycoprotein; Multidrug resistance; Membrane transport; ABC protein; Cancer chemotherapy
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Life Sciences
Identification Number: https://doi.org/10.1016/j.bcp.2016.10.002
Depositing User: Kerr, Ian
Date Deposited: 10 Feb 2017 14:45
Last Modified: 10 Feb 2017 14:47
URI: http://eprints.nottingham.ac.uk/id/eprint/40519

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