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Understanding polyspecificity within the substrate‐binding cavity of the human multidrug resistance P‐glycoprotein
Author(s) -
Martinez Lorena,
Arnaud Ophélie,
Henin Emilie,
Tao Houchao,
Chaptal Vincent,
Doshi Rupak,
Andrieu Thibault,
Dussurgey Sébastien,
Tod Michel,
Di Pietro Attilio,
Zhang Qinghai,
Chang Geoffrey,
Falson Pierre
Publication year - 2014
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12613
Subject(s) - enantiomer , p glycoprotein , multiple drug resistance , sss* , binding site , stereochemistry , chemistry , bioavailability , pharmacology , biology , drug resistance , medicine , biochemistry , genetics
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 QZ 59, 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 QZ 59 inhibition mechanisms of Hoechst 33342 and daunorubicin transports, characterized here in cellulo . We found that QZ 59‐ SSS competes efficiently with both substrates, with K I ,app values of 0.15 and 0.3 μ m , which are 13 and 2 times lower, respectively, than the corresponding K m,app values. In contrast, QZ 59‐ RRR non‐competitively inhibited daunorubicin transport with moderate efficacy ( K I ,app = 1.9 μ m ); it also displayed a mixed‐type inhibition of the Hoechst 33342 transport, resulting from a main non‐competitive tendency ( K i2,app = 1.6 μ m ) and a limited competitive tendency ( K i1,app = 5 μ m ). These results suggest a positional overlap of QZ 59 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 QZ 59‐ SSS locations while the R site overlaps the most embedded location.