Pore-Exposed Tyrosine Residues of P-Glycoprotein Are Important Hydrogen-Bonding Partners for Drugs

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 su...

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Bibliographic Details
Published in:Molecular pharmacology 2014-03, Vol.85 (3), p.420-428
Main Authors: Dönmez Cakil, Yaprak, Khunweeraphong, Narakorn, Parveen, Zahida, Schmid, Diethart, Artaker, Matthias, Ecker, Gerhard F., Sitte, Harald H., Pusch, Oliver, Stockner, Thomas, Chiba, Peter
Format: Article
Language:English
Subjects:
ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics
ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism
Binding Sites - genetics
Cell Line
HEK293 Cells
Humans
Hydrogen - metabolism
Hydrogen Bonding
Ligands
Mutation - genetics
Propafenone - metabolism
Protein Structure, Tertiary - genetics
Tyrosine - genetics
Tyrosine - metabolism
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Summary: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.
ISSN:0026-895X
1521-0111
DOI:10.1124/mol.113.088526