Understanding polyspecificity within the substrate‐binding cavity of the human multidrug resistance P‐glycoprotein. (17th January 2014)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: FEBS journal. Volume 281:Number 3(2014)
• Page Start: 673
• Page End: 682
• Publication Date: 2014-01-17
• Subjects: Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.12613
• Languages: English
• ISSNs: 1742-464X

Abstract

<abstract abstract-type="main" id="febs12613-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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 <italic>SSS</italic> enantiomers or one <italic>RRR</italic> 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 <italic>et al</italic>. (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 <italic>in cellulo</italic>. We found that QZ59‐<italic>SSS</italic> competes efficiently with both substrates, with <italic>K</italic><sub>I</sub><sub>, app</sub> values of 0.15 and 0.3 μ<sc>m</sc>, which are 13 and 2 times lower, respectively, than the corresponding <italic>K</italic><sub>m, app</sub> values. In contrast, QZ59‐<italic>RRR</italic> non‐competitively inhibited daunorubicin transport with moderate efficacy (<italic>K</italic><sub>I</sub><sub>, app </sub>= 1.9 μ<sc>m</sc>); it also displayed a mixed‐type inhibition of the Hoechst 33342 transport, resulting from a main non‐competitive tendency (<italic>K</italic><sub>i2, app </sub>= 1.6 μ<sc>m</sc>) and a limited competitive tendency (<italic>K</italic><sub>i1, app </sub>= 5 μ<sc>m</sc>). These results suggest a positional overlap of QZ59 and drugs binding sites: full for the <italic>SSS</italic> enantiomer and partial for the <italic>RRR</italic> enantiomer. Crystal structure analysis suggests that the H site overlaps both QZ59‐<italic>SSS</italic> locations while the R site overlaps the most embedded location.</p> </abstract>