Show simple item record

dc.contributor.authorSasitharan, K
dc.contributor.authorIqbal, HA
dc.contributor.authorBifsa, F
dc.contributor.authorOlszewska, A
dc.contributor.authorLinton, KJ
dc.identifier.citationSasitharan, K.; Iqbal, H.A.; Bifsa, F.; Olszewska, A.; Linton, K.J. ABCB1 Does Not Require the Side-Chain Hydrogen-Bond Donors Gln347, Gln725, Gln990 to Confer Cellular Resistance to the Anticancer Drug Taxol. Int. J. Mol. Sci. 2021, 22, 8561. ijms22168561en_US
dc.description.abstractThe multidrug efflux transporter ABCB1 is clinically important for drug absorption and distribution and can be a determinant of chemotherapy failure. Recent structure data shows that three glutamines donate hydrogen bonds to coordinate taxol in the drug binding pocket. This is consistent with earlier drug structure-activity relationships that implicated the importance of hydrogen bonds in drug recognition by ABCB1. By replacing the glutamines with alanines we have tested whether any, or all, of Gln347, Gln725, and Gln990 are important for the transport of three different drug classes. Flow cytometric transport assays show that Q347A and Q990A act synergistically to reduce transport of Calcein-AM, BODIPY-verapamil, and OREGON GREEN-taxol bisacetate but the magnitude of the effect was dependent on the test drug and no combination of mutations completely abrogated function. Surprisingly, Q725A mutants generally improved transport of Calcein-AM and BODIPYverapamil, suggesting that engagement of the wild-type Gln725 in a hydrogen bond is inhibitory for the transport mechanism. To test transport of unmodified taxol, stable expression of Q347/725A and the triple mutant was engineered and shown to confer equivalent resistance to the drug as the wild-type transporter, further indicating that none of these potential hydrogen bonds between transporter and transport substrate are critical for the function of ABCB1. The implications of the data for plasticity of the drug binding pocket are discussed.en_US
dc.relation.ispartofInternational Journal of Molecular Sciences
dc.rightsCreative Commons Attribution (CC BY) license
dc.subjectmultidrug resistanceen_US
dc.subjectdrug transporten_US
dc.subjectABC transporteren_US
dc.titleABCB1 Does Not Require the Side-Chain Hydrogen-Bond Donors Gln347, Gln725, Gln990 to Confer Cellular Resistance to the Anticancer Drug Taxolen_US
dc.rights.holder© 2021 by the authors.
pubs.notesNot knownen_US
rioxxterms.funderDefault funderen_US
rioxxterms.identifier.projectDefault projecten_US

Files in this item


This item appears in the following Collection(s)

Show simple item record

Creative Commons Attribution (CC BY) license
Except where otherwise noted, this item's license is described as Creative Commons Attribution (CC BY) license