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

Mittra, Rituparna; Pavy, Megan; Subramanian, Nanditha; George, Anthony M.; O'Mara, Megan L.; Kerr, Ian D.; Callaghan, Richard

Authors

Rituparna Mittra

Megan Pavy

Nanditha Subramanian

Anthony M. George

Megan L. O'Mara

Ian D. Kerr

Richard Callaghan



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.

Citation

Mittra, R., Pavy, M., Subramanian, N., George, A. M., O'Mara, M. L., Kerr, I. D., & Callaghan, R. (2017). Location of contact residues in pharmacologically distinct drug binding sites on P-glycoprotein. Biochemical Pharmacology, 123, https://doi.org/10.1016/j.bcp.2016.10.002

Journal Article Type Article
Acceptance Date Oct 6, 2016
Online Publication Date Oct 8, 2016
Publication Date Jan 1, 2017
Deposit Date Feb 10, 2017
Publicly Available Date Feb 10, 2017
Journal Biochemical Pharmacology
Print ISSN 0006-2952
Electronic ISSN 0006-2952
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 123
DOI https://doi.org/10.1016/j.bcp.2016.10.002
Keywords P-glycoprotein; Multidrug resistance; Membrane transport; ABC protein; Cancer chemotherapy
Public URL http://eprints.nottingham.ac.uk/id/eprint/40519
Publisher URL http://www.sciencedirect.com/science/article/pii/S000629521630346X
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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