1mtb
From Proteopedia
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Viability of a drug-resistant HIV-1 protease mutant: structural insights for better antiviral therapy
Overview
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.
About this Structure
1MTB is a Single protein structure of sequence from Human immunodeficiency virus 1 with QNC and DIQ as ligands. Active as HIV-1 retropepsin, with EC number 3.4.23.16 Full crystallographic information is available from OCA.
Reference
Viability of a drug-resistant human immunodeficiency virus type 1 protease variant: structural insights for better antiviral therapy., Prabu-Jeyabalan M, Nalivaika EA, King NM, Schiffer CA, J Virol. 2003 Jan;77(2):1306-15. PMID:12502847
Page seeded by OCA on Thu Nov 8 14:20:29 2007
