4gye | pdb_00004gye

MDR 769 HIV-1 Protease in Complex with Reduced P1F

spinqualitylabelsall models 4gye, resolution 2.27Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4gye is a 3 chain structure with sequence from Human immunodeficiency virus 1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ILO, NLE, PUK Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q9QM22_9HIV1 Publication Abstract from PubMed Proper proteolytic processing of the HIV-1 Gag/Pol polyprotein is required for HIV infection and viral replication. This feature has made HIV-1 protease an attractive target for antiretroviral drug design for the treatment of HIV-1 infected patients. To examine the role of the P1 and P1'positions of the substrate in inhibitory efficacy of multi-drug resistant HIV-1 protease 769 (MDR 769), we performed a series of structure-function studies. Using the original CA/p2 cleavage site sequence, we generated heptapeptides containing one reduced peptide bond with an L to F and A to F double mutation at P1 and P1' (F-r-F), and an A to F at P1' (L-r-F) resulting in P1/P1' modified ligands. Here, we present an analysis of co-crystal structures of CA/p2 F-r-F, and CA/p2 L-r-F in complex with MDR 769. To examine conformational changes in the complex structure, molecular dynamic (MD) simulations were performed with MDR769-ligand complexes. MD trajectories show the isobutyl group of both the lopinavir analog and the CA/p2 L-r-F substrate cause a conformational change of in the active site of MDR 769. IC50 measurements suggest the non identical P1/P1' ligands (CA/p2 L-r-F and lopinavir analog) are more effective against MDR proteases as opposed to identical P1/P1'ligands. Our results suggest that a non identical P1/P1'composition may be more favorable for the inhibition of MDR 769 as they induce conformational changes in the active site of the enzyme resulting in disruption of the two-fold symmetry of the protease, thus, stabilizing the inhibitor in the active site. Ligand modifications to reduce the relative resistance of multi-drug resistant HIV-1 protease.,Dewdney TG, Wang Y, Liu Z, Sharma SK, Reiter SJ, Brunzelle JS, Kovari IA, Woster PM, Kovari LC Bioorg Med Chem. 2013 Sep 27. pii: S0968-0896(13)00825-0. doi:, 10.1016/j.bmc.2013.09.045. PMID:24128815 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Immunodeficiency virus protease 3D structures

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