4GZF

Multi-drug resistant HIV-1 protease 769 variant with reduced LrF peptide

Summary for 4GZF

• Entry DOI: 10.2210/pdb4gzf/pdb
• Related: 4GYE
• Related PRD ID: PRD_000777
• Descriptor: Protease, LrF peptide (3 entities in total)
• Functional Keywords: multi-drug resistance, protease inhibitor, drug resistance, substrate peptides, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus 1; More
• Total number of polymer chains: 3
• Total formula weight: 22375.41

Authors

Dewdney, T.G.,Wang, Y.,Kovari, I.A.,Brunzelle, J.S.,Reiter, S.J.,Kovari, L.C. (deposition date: 2012-09-06, release date: 2013-10-30, Last modification date: 2023-11-15)

Primary citation

Dewdney, T.G.,Wang, Y.,Liu, Z.,Sharma, S.K.,Reiter, S.J.,Brunzelle, J.S.,Kovari, I.A.,Woster, P.M.,Kovari, L.C.
Ligand modifications to reduce the relative resistance of multi-drug resistant HIV-1 protease.
Bioorg.Med.Chem., 21:7430-7434, 2013

PubMed Abstract: 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.

PubMed: 24128815
DOI: 10.1016/j.bmc.2013.09.045

Experimental method

X-RAY DIFFRACTION (2.05 Å)