Rituparna Mittra
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
Megan Pavy
Nanditha Subramanian
Anthony M. George
Megan L. O'Mara
IAN KERR ian.kerr@nottingham.ac.uk
Associate Professor
Richard Callaghan
Abstract
© 2016 Elsevier Inc. 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, 19-28. 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 | Mar 29, 2024 |
Journal | Biochemical Pharmacology |
Print ISSN | 0006-2952 |
Electronic ISSN | 1873-2968 |
Publisher | Elsevier |
Peer Reviewed | Peer Reviewed |
Volume | 123 |
Pages | 19-28 |
DOI | https://doi.org/10.1016/j.bcp.2016.10.002 |
Keywords | P-glycoprotein; Multidrug resistance; Membrane transport; ABC protein; Cancer chemotherapy |
Public URL | https://nottingham-repository.worktribe.com/output/830822 |
Publisher URL | http://www.sciencedirect.com/science/article/pii/S000629521630346X |
Additional Information | This article is maintained by: Elsevier; Article Title: Location of contact residues in pharmacologically distinct drug binding sites on P-glycoprotein; Journal Title: Biochemical Pharmacology; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.bcp.2016.10.002; Content Type: article; Copyright: © 2016 Elsevier Inc. All rights reserved. |
Files
Mittra-revised.pdf
(982 Kb)
PDF
You might also like
Function of the pseudo phosphotransfer proteins has diverged between rice and Arabidopsis
(2021)
Journal Article
Y-box binding protein-1: A neglected target in pediatric brain tumors?
(2020)
Journal Article
Downloadable Citations
About Repository@Nottingham
Administrator e-mail: digital-library-support@nottingham.ac.uk
This application uses the following open-source libraries:
SheetJS Community Edition
Apache License Version 2.0 (http://www.apache.org/licenses/)
PDF.js
Apache License Version 2.0 (http://www.apache.org/licenses/)
Font Awesome
SIL OFL 1.1 (http://scripts.sil.org/OFL)
MIT License (http://opensource.org/licenses/mit-license.html)
CC BY 3.0 ( http://creativecommons.org/licenses/by/3.0/)
Powered by Worktribe © 2024
Advanced Search