Understanding polyspecificity within the substrate-binding cavity of the human multidrug resistance P-glycoprotein.

ABSTRACT: Human P-glycoprotein (P-gp) controls drugs bioavailability by pumping structurally unrelated drugs out of cells. The X-ray structure of the mouse P-gp ortholog has been solved, with two SSS enantiomers or one RRR enantiomer of the selenohexapeptide inhibitor QZ59, found within the putative drug-binding pocket (Aller SG, Yu J, Ward A, Weng Y, Chittaboina S, Zhuo R, Harrell PM, Trinh YT, Zhang Q, Urbatsch IL et al. (2009). Science 323, 1718-1722). This offered the first opportunity to localize the well-known H and R drug-binding sites with respect to the QZ59 inhibition mechanisms of Hoechst 33342 and daunorubicin transports, characterized here in cellulo. We found that QZ59-SSS competes efficiently with both substrates, with K(I,app) values of 0.15 and 0.3 μM, which are 13 and 2 times lower

SUBMITTER: Martinez L 

PROVIDER: S-EPMC5663232 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature