TAILIEUCHUNG - Báo cáo khoa học: Comparison of the inward- and outward-open homology models and ligand binding of human P-glycoprotein

An homology model of human P-glycoprotein, based on the X-ray struc-ture 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 cav-ity are identified and compared with those in the outward-facing confor-mation of human P-glycoprotein developed previously based on the Sav1866 structure. | Comparison of the inward- and outward-open homology models and ligand binding of human P-glycoprotein Ilza K. Pajeva1 2 Christoph Globisch1 and Michael Wiese1 1 Pharmaceutical institute University of Bonn Germany 2 Center of BiomedicalEngineering Bulgarian Academy of Science Sofia Bulgaria Keywords binding sites homology model ligand interactions multidrug resistance P-glycoprotein Correspondence M. Wiese Pharmaceutical institute University of Bonn An der Immenburg 4 53121 Bonn Germany Fax 49 228 737929 Tel 49 228 735213 E-mail mwiese@ These authors contributed equally to this work Received 7 August 2009 revised 21 September 2009 accepted 29 September 2009 doi 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 outwardfacing 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 .

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