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

The FEBS journal 2014 Feb

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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, respectively, than the corresponding K(m,app) values. In contrast, QZ59-RRR non-competitively inhibited daunorubicin transport with moderate efficacy (K(I,app) = 1.9 μM); it also displayed a mixed-type inhibition of the Hoechst 33342 transport, resulting from a main non-competitive tendency (K(i2,app) = 1.6 μM) and a limited competitive tendency (K(i1,app) = 5 μM). These results suggest a positional overlap of QZ59 and drugs binding sites: full for the SSS enantiomer and partial for the RRR enantiomer. Crystal structure analysis suggests that the H site overlaps both QZ59-SSS locations while the R site overlaps the most embedded location. © 2013 FEBS.

Citation

Lorena Martinez, Ophélie Arnaud, Emilie Henin, Houchao Tao, Vincent Chaptal, Rupak Doshi, Thibault Andrieu, Sébastien Dussurgey, Michel Tod, Attilio Di Pietro, Qinghai Zhang, Geoffrey Chang, Pierre Falson. Understanding polyspecificity within the substrate-binding cavity of the human multidrug resistance P-glycoprotein. The FEBS journal. 2014 Feb;281(3):673-82