1MTB: Viability Of A Drug-resistant Hiv-1 Protease Mutant: Structural Insights For Better Antiviral Therapy

Citation:
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.
PDB ID: 1MTBDownload
MMDB ID: 21784
PDB Deposition Date: 2002/9/20
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 2.5  Å
Source Organism:
Similar Structures:
Biological Unit for 1MTB: dimeric; determined by author and by software (PISA)
Molecular Components in 1MTB
Label Count Molecule
Proteins (2 molecules)
2
Protease Retropepsin
Molecule annotation
Chemicals (4 molecules)
1
1
2
1
3
1
4
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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