| Comparison of the inward- and outward-open homology models and ligand binding of human P-glycoprotein. | |
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MedLine Citation:
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PMID: 19878299 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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An homology model of human P-glycoprotein, based on the X-ray structure of the recently resolved mouse P-glycoprotein, is presented. The model corresponds to the inward-facing conformation competent for drug binding. From the model, the residues involved in the protein-binding cavity are identified and compared with those in the outward-facing conformation of human P-glycoprotein developed previously based on the Sav1866 structure. A detailed analysis of the interactions of the cyclic peptides QZ59-RRR and QZ59-SSS is presented in both the X-ray structures of mouse P-glycoprotein and the human P-glycoprotein model generated by ligand docking. The results confirm the functional role of transmembrane domains TM4, TM6, TM10 and TM12 as entrance gates to the protein cavity, and also imply differences in their functions. The analysis of the cavities in both models suggests that the ligands remain bound to the same residues during the transition from the inward- to the outward-facing conformations. The analysis of the ligand-protein interactions in the X-ray complexes shows differences in the residues involved, as well as in the specific interactions performed by the same ligand within the same protein. This observation is supported by docking of the QZ59 ligands into human P-glycoprotein, thus aiding in the understanding of the complex behavior of P-glycoprotein substrates and inhibitors. The results confirm the possibility for multispecific drug interactions of the protein, and are important for elucidating the P-glycoprotein function and ligand interactions. |
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Authors:
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Ilza K Pajeva; Christoph Globisch; Michael Wiese |
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Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't Date: 2009-10-29 |
Journal Detail:
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Title: The FEBS journal Volume: 276 ISSN: 1742-4658 ISO Abbreviation: FEBS J. Publication Date: 2009 Dec |
Date Detail:
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Created Date: 2010-01-12 Completed Date: 2010-02-12 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101229646 Medline TA: FEBS J Country: England |
Other Details:
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Languages: eng Pagination: 7016-26 Citation Subset: IM |
Affiliation:
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Pharmaceutical Institute, University of Bonn, Germany. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Sequence Animals Binding Sites Crystallography, X-Ray Humans Ligands Mice Models, Molecular Molecular Sequence Data P-Glycoprotein / antagonists & inhibitors, chemistry*, metabolism* Peptides, Cyclic / chemistry*, metabolism Protein Conformation Structural Homology, Protein Structure-Activity Relationship Substrate Specificity |
| Chemical | |
Reg. No./Substance:
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0/Ligands; 0/P-Glycoprotein; 0/Peptides, Cyclic; 0/cyclic-tris-(R)-valineselenazole |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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