4GZF: Multi-drug Resistant Hiv-1 Protease 769 Variant With Reduced Lrf Peptide

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.
PDB ID: 4GZFDownload
MMDB ID: 114655
PDB Deposition Date: 2012/9/6
Updated in MMDB: 2013/11
Experimental Method:
x-ray diffraction
Resolution: 2.05  Å
Source Organism:
synthetic construct
Similar Structures:
Biological Unit for 4GZF: trimeric; determined by author and by software (PISA)
Molecular Components in 4GZF
Label Count Molecule
Proteins (3 molecules)
Molecule annotation
LRF Peptide
Molecule annotation
* Click molecule labels to explore molecular sequence information.

Citing MMDB