1izh

Inhibitor of HIV protease with unusual binding mode potently inhibiting multi-resistant protease mutants

spinqualitylabelsall models 1izh, resolution 1.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 1izh is a 2 chain structure with sequence from Human immunodeficiency virus 1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.9Å Ligands: Q50 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q90EB9_9HIV1 Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed Protease inhibitors (PIs) are an important class of drugs for the treatment of HIV infection. However, in the course of treatment, resistant viral variants with reduced sensitivity to PIs often emerge and become a major obstacle to successful control of viral load. On the basis of a compound equipotently inhibiting HIV-1 and 2 proteases (PR), we have designed a pseudopeptide inhibitor, QF34, that efficiently inhibits a wide variety of PR variants. In order to analyze the potency of the inhibitor, we constructed PR species harboring the typical (signature) mutations that confer resistance to commercially available PIs. Kinetic analyses showed that these mutated PRs were inhibited up to 1,000-fold less efficiently by the clinically approved PIs. In contrast, all PR species were effectively inhibited by QF34. In a clinical study, we have monitored 30 HIV-positive patients in the Czech Republic undergoing highly active antiretroviral therapy, and have identified highly PI resistant variants. Kinetic analyses revealed that QF34 retained its subnanomolar potency against multi-drug resistant PR variants. X-ray crystallographic analysis and molecular modeling experiments explained the wide specificity of QF34: this inhibitor binds to the PR in an unusual manner, thus avoiding contact sites that are mutated upon resistance development, and the unusual binding mode and consequently the binding energy is therefore preserved in the complex with a resistant variant. These results suggest a promising route for the design of second-generation PIs that are active against a variety of resistant PR variants. Unusual binding mode of an HIV-1 protease inhibitor explains its potency against multi-drug-resistant virus strains.,Weber J, Mesters JR, Lepsik M, Prejdova J, Svec M, Sponarova J, Mlcochova P, Skalicka K, Strisovsky K, Uhlikova T, Soucek M, Machala L, Stankova M, Vondrasek J, Klimkait T, Kraeusslich HG, Hilgenfeld R, Konvalinka J J Mol Biol. 2002 Dec 6;324(4):739-54. PMID:12460574 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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