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The translocation mechanism of P‐glycoprotein
Author(s) -
Callaghan Richard,
Ford Robert C.,
Kerr Ian D.
Publication year - 2006
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2005.11.083
Subject(s) - chromosomal translocation , efflux , p glycoprotein , multiple drug resistance , transporter , atp binding cassette transporter , function (biology) , mechanism (biology) , atp hydrolysis , biology , chemistry , biochemistry , computational biology , drug resistance , microbiology and biotechnology , enzyme , genetics , gene , philosophy , epistemology , atpase
Multidrug transporters are involved in mediating the failure of chemotherapy in treating several serious diseases. The archetypal multidrug transporter P‐glycoprotein (P‐gp) confers resistance to a large number of chemically and functionally unrelated anti‐cancer drugs by mediating efflux from cancer cells. The ability to efflux such a large number of drugs remains a biological enigma and the lack of mechanistic understanding of the translocation pathway used by P‐gp prevents rational design of compounds to inhibit its function. The translocation pathway is critically dependent on ATP hydrolysis and drug interaction with P‐gp is possible at one of a multitude of allosterically linked binding sites. However, aspects such as coupling stoichiometry, molecular properties of binding sites and the nature of conformational changes remain unresolved or the centre of considerable controversy. The present review attempts to utilise the available data to generate a detailed sequence of events in the translocation pathway for this dexterous protein.