2aqu

From Proteopedia

Revision as of 15:14, 15 February 2008

Structure of HIV-1 protease bound to atazanavir

Overview

A series of HIV-1 protease mutants has been designed in an effort to, analyze the contribution to drug resistance provided by natural, polymorphisms as well as therapy-selective (active and non-active site), mutations in the HIV-1 CRF_01 A/E (AE) protease when compared to that of, the subtype B (B) protease. Kinetic analysis of these variants using, chromogenic substrates showed differences in substrate specificity between, pretherapy B and AE proteases. Inhibition analysis with ritonavir, indinavir, nelfinavir, amprenavir, saquinavir, lopinavir, and atazanavir, revealed that the natural polymorphisms found in A/E can influence, inhibitor resistance. It was also apparent that a high level of resistance, in the A/E protease, as with B protease, is due to it aquiring a, combination of active site and non-active site mutations. Structural, analysis of atazanavir bound to a pretherapy B protease showed that the, ability of atazanavir to maintain its binding affinity for variants, containing some resistance mutations is due to its unique interactions, with flap residues. This structure also explains why the I50L and I84V, mutations are important in decreasing the binding affinity of atazanavir.

About this Structure

2AQU is a Single protein structure of sequence from Human immunodeficiency virus 1 with as ligand. Active as HIV-1 retropepsin, with EC number 3.4.23.16 Full crystallographic information is available from OCA.

Reference

Analysis of HIV-1 CRF_01 A/E protease inhibitor resistance: structural determinants for maintaining sensitivity and developing resistance to atazanavir., Clemente JC, Coman RM, Thiaville MM, Janka LK, Jeung JA, Nukoolkarn S, Govindasamy L, Agbandje-McKenna M, McKenna R, Leelamanit W, Goodenow MM, Dunn BM, Biochemistry. 2006 May 2;45(17):5468-77. PMID:16634628

Page seeded by OCA on Fri Feb 15 17:14:45 2008