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Mol Pharmacol. 2014 Mar;85(3):420-8. doi: 10.1124/mol.113.088526. Epub 2013 Dec 23.

Pore-exposed tyrosine residues of P-glycoprotein are important hydrogen-bonding partners for drugs.

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Institutes of Medical Chemistry (Y.D.C., N.K., Z.P., P.C.), Pharmacology (Y.D.C., H.H.S., T.S.), and Physiology (D.S.), Department of Medical Biochemistry, Max F. Perutz Laboratories (M.A.), and Department of Cell and Developmental Biology (O.P.), Medical University of Vienna, Vienna, Austria; Department of Biochemistry, Abdul Wali Khan University Mardan, Pakistan (Z.P.); and Emerging Field Pharmacoinformatics, Department of Medicinal Chemistry, University of Vienna, Vienna, Austria (G.F.E.).


The multispecific efflux transporter, P-glycoprotein, plays an important role in drug disposition. Substrate translocation occurs along the interface of its transmembrane domains. The rotational C2 symmetry of ATP-binding cassette transporters implies the existence of two symmetry-related sets of substrate-interacting amino acids. These sets are identical in homodimeric transporters, and remain evolutionary related in full transporters, such as P-glycoprotein, in which substrates bind preferentially, but nonexclusively, to one of two binding sites. We explored the role of pore-exposed tyrosines for hydrogen-bonding interactions with propafenone type ligands in their preferred binding site 2. Tyrosine 953 is shown to form hydrogen bonds not only with propafenone analogs, but also with the preferred site 1 substrate rhodamine123. Furthermore, an accessory role of tyrosine 950 for binding of selected propafenone analogs is demonstrated. The present study demonstrates the importance of domain interface tyrosine residues for interaction of small molecules with P-glycoprotein.

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