Evidence for modulatory sites at the lipid-protein interface of the human multidrug transporter P-glycoprotein.

Biochemistry
Debjani MandalS Dey

Abstract

The human multidrug transporter P-glycoprotein (Pgp or ABCB1) sets up pharmacological barriers to many clinically important drugs, a therapeutic remedy for which has yet to be formulated. For the rational design of mechanism-based inhibitors (or modulators), it is necessary to map the potential sites for modulator interaction and understand their modes of communication with the other functional domains of Pgp. In this study, combining directed mutagenesis with homology modeling, we provide evidence of two modulator-specific sites at the lipid protein interface of Pgp. Targeting 21 variant positions in the COOH-terminal transmembrane (TM) regions, we find residues M948 (in TM11) and F983, M986, V988, and Q990 (all four in TM12) critically involved in substrate-site modulation by a thioxanthene-based allosteric modulator cis-(Z)-flupentixol. Interestingly, for ATP-site modulation by the same modulator, only two (M948 and Q990) of those four residues appear indispensable, together with two additional residues, T837 and I864 in TM9 and TM10, respectively, suggesting independent modes of communication linking the allosteric site with the substrate binding and ATPase domains. None of the seven residues identified prove to be critical...Continue Reading

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Citations

Jun 28, 2013·Journal of Chemical Information and Modeling·Ricardo J FerreiraDaniel J V A dos Santos
Mar 8, 2016·European Journal of Pharmacology·Jiwon Kim, Jin-Ho Song
Dec 10, 2015·BioMed Research International·Karobi Moitra
Jun 13, 2017·Pharmacology Research & Perspectives·Matthias SporkThomas Stockner

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