The translocation mechanism of P-glycoprotein.
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.
Callaghan
Richard
R
Nuffield Department of Clinical Laboratory Sciences, Level 4, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, United Kingdom. richard.callaghan@ndcls.ox.ac.uk
Ford
Robert C
RC
Kerr
Ian D
ID
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism / Q000502:physiology*; D000255:Adenosine Triphosphate / Q000378:metabolism; D006868:Hydrolysis; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010710:Phosphates / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004364:Pharmaceutical Preparations; D010710:Phosphates; D000255:Adenosine Triphosphate