Abstract
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
Current Medicinal Chemistry
Title: 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
Volume: 13 Issue: 7
Author(s): Peter Chiba, Ivana Mihalek, Gerhard F. Ecker, Stephan Kopp and Olivier Lichtarge
Affiliation:
Keywords: P-glycoprotein, photoaffinity labeling, mass spectrometry, site directed mutagenesis, in silico conservation prediction
Abstract: 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.
Export Options
About this article
Cite this article as:
Chiba Peter, Mihalek Ivana, Ecker F. Gerhard, Kopp Stephan and Lichtarge Olivier, 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, Current Medicinal Chemistry 2006; 13 (7) . https://dx.doi.org/10.2174/092986706776055607
DOI https://dx.doi.org/10.2174/092986706776055607 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Regression of Oxidative Stress by Targeting eNOS and Nrf2/ARE Signaling: A Guided Drug Target for Cardiovascular Diseases
Current Topics in Medicinal Chemistry Ribonucleotide Reductase: A Critical Enzyme for Cancer Chemotherapy and Antiviral Agents
Recent Patents on Anti-Cancer Drug Discovery Safety Considerations Associated with Development and Clinical Application of Lentiviral Vector Systems for Gene Transfer
Current Genomics Click Chemistry Based Functionalizations of Nucleoside, Nucleotide and Nucleic Acids
Current Organic Chemistry Exploration of the Medicinal Peptide Space
Protein & Peptide Letters Lung Cancer Vaccines
Current Gene Therapy Synthesis, Biological Evaluation and Molecular Docking Studies of Pyridine Incorporated Chalcone Derivatives as Anticancer Agents
Letters in Organic Chemistry Metallothioneins and Platinum(II) Anti-Tumor Compounds
Current Medicinal Chemistry Mitochondrial Dynamics: An Emerging Paradigm in Ischemia-Reperfusion Injury
Current Pharmaceutical Design Recent Advances in the New Generation Taxane Anticancer Agents
Medicinal Chemistry DNA Methylation and Breast Cancer
Current Genomics The Calcium-Sensing Receptor as a Regulator of Cellular Fate in Normal and Pathological Conditions
Current Molecular Medicine Extracellular Ca<sup>2+</sup> Selectively Enhances Adriamycin-induced Cell Death in Human Hepatoma Cells
Current Cancer Drug Targets The Rationale of Targeting Neutrophils with Dapsone during Glioblastoma Treatment
Anti-Cancer Agents in Medicinal Chemistry The Intriguing Interplay Between Therapies Targeting the Epidermal Growth Factor Receptor, the Hypoxic Microenvironment and Hypoxia-inducible Factors
Current Pharmaceutical Design Lipoprotein Like Nanoparticles Used in Drug and Gene Delivery
Current Pharmaceutical Design Thalidomide: An Overview of its Pharmacological Mechanisms of Action
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Recent Progress in Medicinal Investigations on Trichosanthin and other Ribosome Inactivating Proteins from the Plant Genus Trichosanthes
Current Medicinal Chemistry Investigation of the pH Dependent Cytotoxicity of Paclitaxel Conjugated Gold Nanoparticles
Pharmaceutical Nanotechnology Prodrugs in Photodynamic Anticancer Therapy
Current Pharmaceutical Design