PT  - JOURNAL ARTICLE
AU  - Catherine Martin
AU  - Georgina Berridge
AU  - Christopher F. Higgins
AU  - Prakash Mistry
AU  - Peter Charlton
AU  - Richard Callaghan
TI  - Communication between Multiple Drug Binding Sites on P-glycoprotein
AID  - 10.1124/mol.58.3.624
DP  - 2000 Sep 01
TA  - Molecular Pharmacology
PG  - 624--632
VI  - 58
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/58/3/624.short
4100  - http://molpharm.aspetjournals.org/content/58/3/624.full
SO  - Mol Pharmacol2000 Sep 01; 58
AB  - P-glycoprotein, a member of the ATP-binding cassette transporter family, is able to confer resistance on tumors against a large number of functionally and chemically distinct cytotoxic compounds. Several recent investigations suggest that P-glycoprotein contains multiple drug binding sites rather than a single site of broad substrate specificity. In the present study, radioligand-binding techniques were used to directly characterize drug interaction sites on P-glycoprotein and how these multiple sites interact. The drugs used were classified as either 1) substrates, which are known to be transported by P-glycoprotein (e.g., vinblastine) or 2) modulators, which alter P-glycoprotein function but are not themselves transported by the protein (e.g., XR9576). Drug interactions with P-glycoprotein were either competitive, at a common site, or noncompetitive, and therefore at distinct sites. Based on these data, we can assign a minimum of four drug binding sites on P-glycoprotein. These sites fall into two categories: transport, at which translocation of drug across the membrane can occur, and regulatory sites, which modify P-glycoprotein function. Intriguingly, however, some modulators interact with P-glycoprotein at a transport site rather than a regulatory site. The pharmacological data also demonstrate that both transport and regulatory sites are able to switch between high- and low-affinity conformations. The multiple sites on P-glycoprotein display complex allosteric interactions through which interaction of drug at one site switches other sites between high- or low-affinity conformations. The data are discussed in terms of a model for the mechanism of transport by P-glycoprotein.