RT Journal Article SR Electronic T1 Pore Exposed Tyrosine Residues of P-glycoprotein are Important Hydrogen Bonding Partners for Drugs JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP mol.113.088526 DO 10.1124/mol.113.088526 A1 Yaprak Donmez Cakil A1 Narakorn Khunweeraphong A1 Zahida Parveen A1 Diethart Schmid A1 Matthias Artaker A1 Gerhard F Ecker A1 Harald H Sitte A1 Oliver Pusch A1 Thomas Stockner A1 Peter Chiba YR 2013 UL http://molpharm.aspetjournals.org/content/early/2013/12/23/mol.113.088526.abstract AB 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 ABC-transporters implies the existence of two symmetry related sets of substrate-interacting amino acids. These sets are identical in homodimeric transporters, and remain evolutionarily related in full transporters such as P-glycoprotein, where substrates bind preferentially, but non-exclusively 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 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.