1MTB

Viability of a drug-resistant HIV-1 protease mutant: structural insights for better antiviral therapy

Summary for 1MTB

• Entry DOI: 10.2210/pdb1mtb/pdb
• Related: 1F7A 1HXB 1MT7 1MT8 1MT9
• Related PRD ID: PRD_000454
• Descriptor: PROTEASE RETROPEPSIN, (2S)-N-[(2S,3R)-4-[(2S,3S,4aS,8aS)-3-(tert-butylcarbamoyl)-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-3-hydroxy-1 -phenyl-butan-2-yl]-2-(quinolin-2-ylcarbonylamino)butanediamide (3 entities in total)
• Functional Keywords: hiv-1 protease, drug resistance, substrate recognition, inhibitor binding, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus 1
• Cellular location: Gag-Pol polyprotein: Host cell membrane; Lipid-anchor. Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P03369
• Total number of polymer chains: 2
• Total formula weight: 22270.30

Authors

Prabu-Jeyabalan, M.,Nalivaika, E.A.,King, N.M.,Schiffer, C.A. (deposition date: 2002-09-20, release date: 2003-01-07, Last modification date: 2024-05-29)

Primary citation

Prabu-Jeyabalan, M.,Nalivaika, E.A.,King, N.M.,Schiffer, C.A.
Viability of drug-resistant human immunodeficiency virus type 1 protease variant: structural insights for better antiviral therapy
J.Virol., 77:1305-1315, 2003

PubMed Abstract: Under the selective pressure of protease inhibitor therapy, patients infected with human immunodeficiency virus (HIV) often develop drug-resistant HIV strains. One of the first drug-resistant mutations to arise in the protease, particularly in patients receiving indinavir or ritonavir treatment, is V82A, which compromises the binding of these and other inhibitors but allows the virus to remain viable. To probe this drug resistance, we solved the crystal structures of three natural substrates and two commercial drugs in complex with an inactive drug-resistant mutant (D25N/V82A) HIV-1 protease. Through structural analysis and comparison of the protein-ligand interactions, we found that Val82 interacts more closely with the drugs than with the natural substrate peptides. The V82A mutation compromises these interactions with the drugs while not greatly affecting the substrate interactions, which is consistent with previously published kinetic data. Coupled with our earlier observations, these findings suggest that future inhibitor design may reduce the probability of the appearance of drug-resistant mutations by targeting residues that are essential for substrate recognition.

PubMed: 12502847
DOI: 10.1128/JVI.77.2.1306-1315.2003

Experimental method

X-RAY DIFFRACTION (2.5 Å)