Generic placeholder image

Current Medicinal Chemistry


ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Role of Transmembrane Domain/Transmembrane Domain Interfaces of PGlycoprotein (ABCB1) in Solute Transport. Convergent Information from Photoaffinity Labeling, Site Directed Mutagenesis and in Silico Importance Prediction

Author(s): Peter Chiba, Ivana Mihalek, Gerhard F. Ecker, Stephan Kopp and Olivier Lichtarge

Volume 13, Issue 7, 2006

Page: [793 - 805] Pages: 13

DOI: 10.2174/092986706776055607

Price: $65


Human P-glycoprotein (P-gp, ABCB1) plays an important role in the development of resistance to anticancer therapy. This ABC-transporter (ATP-binding cassette transporter) intercepts drugs at the level of the plasma membrane and effluxes them before they are able to reach their intracellular target structures. Inhibition of P-gp by low molecular weight compounds has been advocated as a concept for resensitization of cells to anticancer agents and several clinical studies in oncological patients have advanced to phase III. Even more importantly, P-glycoprotein also represents an antitarget. Its expression in cells lining the intestinal tract, the canalicular side of hepatocytes, renal tubuli and the blood brain barrier lead to interference with pharmacokinetics of compounds that are recognized as pump substrates. An early prediction of ADMET (Absorption-Distribution-Metabolism-Excretion-Toxicity) properties is important during drug development, since interference of a compound with P-gp might compromise its future development into a drug. Despite considerable efforts, the mechanism by which P-gp binds and transports its solutes remains unclear. Generation of homology models of the protein allowed integration of data obtained by photoaffinity labeling, in silico prediction of functional importance by evolutionary tracing and site directed mutagenesis. An integral view of data indicates that these three lines of evidence converge to indicate two pseudosymmetric P-gp drug binding pockets located at the two transmembrane domain interfaces.

Keywords: P-glycoprotein, photoaffinity labeling, mass spectrometry, site directed mutagenesis, in silico conservation prediction

Rights & Permissions Print Export Cite as
© 2023 Bentham Science Publishers | Privacy Policy