ABCMdb

ABCB1 p.Tyr310Phe

Predicted by SNAP2:	A: D (75%), C: D (59%), D: D (91%), E: D (91%), F: N (53%), G: D (85%), H: D (80%), I: D (71%), K: D (91%), L: D (75%), M: D (71%), N: D (80%), P: D (91%), Q: D (80%), R: D (91%), S: D (85%), T: D (80%), V: D (75%), W: D (66%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D,

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Publications
[hide] Pore-exposed tyrosine residues of P-glycoprotein a... Mol Pharmacol. 2014 Mar;85(3):420-8. doi: 10.1124/mol.113.088526. Epub 2013 Dec 23. Donmez Cakil Y, Khunweeraphong N, Parveen Z, Schmid D, Artaker M, Ecker GF, Sitte HH, Pusch O, Stockner T, Chiba P
Pore-exposed tyrosine residues of P-glycoprotein are important hydrogen-bonding partners for drugs.
Mol Pharmacol. 2014 Mar;85(3):420-8. doi: 10.1124/mol.113.088526. Epub 2013 Dec 23., [PMID:24366667]

Abstract [show]
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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No. Sentence Comment
53 Construction of P-gp Mutants The following primers were used for generation of the Y307F, Y310F, Y307F/Y310F, Y950F, Y953F, and Y950F/Y953F mutations of hexa-His-tagged human P-gp in the entry vector pENTR4: Y307F- forward, 59-CTTTCCTGCTGATCTTTGCATCTTATGCTCTGGCC-39; Y307F-reverse, 59-GGCCAGAGCATAAGATGCAAAGATCAGCAGG AAAG-39; Y310F-forward, 59-CTTTCCTGCTGATCTATGCATCTTT TGCTCTGGCC-39; Y310F-reverse, 59-GGCCAGAGCAAAAGATGCA- TAGATCAGCAGGAAAG-39; Y307F/Y310F-forward, 59-CTTTCCTG CTGATCTTTGCATCTTTTGCTCTGGCC-39; Y307F/Y310F-reverse, 59-GGCCAGAGCAAAAGATGCAAAGATCAGCAGGAAAG-39; Y950F- forward, 59-TCACCCAGGCAATGATGTTTTTTTCCTATGCTGGATG- 39; Y950F-reverse, 59-CATCCAGCATAGGAAAAAAACATCATTGCC TGGGTGA-39; Y953F-forward, 59-ACCCAGGCAATGATGTATTTTT CCTTTGCTGGATGTTTC-39; Y953F-reverse, 59-GAAACATCCAGCAAA GGAAAAATACATCATTGCCTGGGT-39; Y950F/Y953F-forward, 59-CCTT CACCCAGGCAATGATGTTTTTTTCCTTTGCTGGATGTTTCC -39; and Y950F/Y953F-reverse, 59-GGAAACATCCAGCAAAGGAAAAAAACATCA TTGCCTGGGTGAAGG-39. Login to comment
114 All mutants were detected at the plasma membrane, although the expression levels of Q132R/Y950F, Q773R/Y950F, and Y307F/Y310F were reduced (Supplemental Fig. 5). Login to comment