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Characterizing drug interactions in the substrate binding pocket of the P-glycoprotein multidrug efflux pump

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dc.contributor.advisor Sharom, Frances J. Ward, David 2012-02-02T21:17:54Z 2012-02-02T21:17:54Z 2012-02 2012-02-01 2012-02-02
dc.description.abstract P-glycoprotein (Pgp, ABCB1) is a polyspecific efflux transporter implicated in multidrug resistance in human cancers. In this study, tetramethylrhodamine-5-carbonyl azide (AzTMR) was covalently crosslinked to the Pgp drug binding pocket with a stoichiometry of 1. The Pgp-AzTMR adduct was functionally equivalent to unlabelled Pgp and retained its ability to transport Hoechst 33342. The binding site of AzTMR in Pgp was nonpolar, with a similar environment to that of propanol. Pgp-AzTMR could bind a second drug molecule, with a higher affinity for H-site drugs and lower affinity for other R-site drugs. Unlabelled Pgp interacted with dimeric versions of known Pgp modulators, binding them with higher affinity than the monomer. These compounds were also found to either stimulate or inhibit Pgp ATPase activity depending on the concentration. Pgp-AzTMR was able to bind dimeric drugs, indicating that 3 substrate moieties can fit into the binding pocket. en_US
dc.description.sponsorship The Canadian Cancer Society en_US
dc.language.iso en en_US
dc.rights.uri *
dc.subject P-glycoprotein en_US
dc.subject Pgp en_US
dc.subject drug resistance en_US
dc.subject cancer en_US
dc.subject tumour en_US
dc.subject MDR en_US
dc.subject drug binding en_US
dc.subject drug transport en_US
dc.subject multidrug resistance en_US
dc.subject chemotherapy en_US
dc.title Characterizing drug interactions in the substrate binding pocket of the P-glycoprotein multidrug efflux pump en_US
dc.type Thesis en_US Biophysics en_US Master of Science en_US Department of Molecular and Cellular Biology en_US
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