PT  - JOURNAL ARTICLE
AU  - Yaprak Dönmez Cakil
AU  - Narakorn Khunweeraphong
AU  - Zahida Parveen
AU  - Diethart Schmid
AU  - Matthias Artaker
AU  - Gerhard F. Ecker
AU  - Harald H. Sitte
AU  - Oliver Pusch
AU  - Thomas Stockner
AU  - Peter Chiba
TI  - Pore-Exposed Tyrosine Residues of P-Glycoprotein Are Important Hydrogen-Bonding Partners for Drugs
AID  - 10.1124/mol.113.088526
DP  - 2014 Mar 01
TA  - Molecular Pharmacology
PG  - 420--428
VI  - 85
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/85/3/420.short
4100  - http://molpharm.aspetjournals.org/content/85/3/420.full
SO  - Mol Pharmacol2014 Mar 01; 85
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 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.