Determinants of the activity and substrate recognition of breast cancer resistance protein (ABCG2)
| Autor: | Milena Julia Szafraniec, Leszek Fiedor, Małgorzata Szczygieł, Krystyna Urbanska |
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| Rok vydání: | 2014 |
| Předmět: |
BCRP substrates
Abcg2 BCRP inhibitors ATP-binding cassette transporter Breast Neoplasms Substrate Specificity Xenobiotics Protein structure multidrug resistance ATP Binding Cassette Transporter Subfamily G Member 2 Animals Humans Pharmacology (medical) General Pharmacology Toxicology and Pharmaceutics Structural motif biology Transporter Biological Transport BCRP variants Transmembrane protein Drug Resistance Multiple Neoplasm Proteins Transmembrane domain ABC transporters Biochemistry Drug Resistance Neoplasm biology.protein BCRP ATP-Binding Cassette Transporters Female Efflux BCRP regulation |
| Zdroj: | Drug metabolism reviews. 46(4) |
| ISSN: | 1097-9883 |
| Popis: | The xenobiotic transporters are among the most important constituents of detoxification system in living organisms. Breast cancer resistance protein (BCRP/ABCG2) is one of the major transporters involved in the efflux of xenobiotics. To understand its role in chemotherapeutic and multidrug resistance, it is crucial to establish the determinants of its substrate specificity, which obviously is of high relevance for successful therapy of many diseases. This article summarizes the current knowledge about the substrate preferences of BCRP. We overview the factors which determine its activity, inhibition and substrate recognition, focusing on the structural features of the transporter. BCRP substrate specificity is quite low as it interacts with a spectrum of substances with only a few common features: hydrophobic and aromatic regions, possibly a flat conformation and the metal ion-, oxygen- and nitrogen-containing functionalities, most of which may be the donors/acceptors of H-bonds. Several amino acid residues and structural motifs are responsible for BCRP activity and substrate recognition. Thus, the active form of BCRP, at least a dimer or a larger oligomer is maintained by intramolecular disulfide bridge that involves Cys(603) residues. The GXXXG motif in transmembrane helix 1, Cys residues, Arg(482) and Lys(86) are responsible for maintaining the protein structure, which confers transport activity, and the His(457) or Arg(456) residues are directly involved in substrate binding. Arg(482) does not directly bind substrates, but electrostatically interacts with charged molecules, which initiates the conformational changes that transmit the signal from the transmembrane regions to the ABC domain. |
| Databáze: | OpenAIRE |
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