1ztz

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spinqualitylabelsall models 1ztz, resolution 2.15Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal structure of HIV protease- metallacarborane complex

Overview

HIV protease (PR) represents a prime target for rational drug design, and, protease inhibitors (PI) are powerful antiviral drugs. Most of the current, PIs are pseudopeptide compounds with limited bioavailability and, stability, and their use is compromised by high costs, side effects, and, development of resistant strains. In our search for novel PI structures, we have identified a group of inorganic compounds, icosahedral, metallacarboranes, as candidates for a novel class of nonpeptidic PIs., Here, we report the potent, specific, and selective competitive inhibition, of HIV PR by substituted metallacarboranes. The most active compound, sodium hydrogen butylimino bis-8,8-[5-(3-oxa-pentoxy)-3-cobalt, bis(1,2-dicarbollide)]di-ate, exhibited a K(i) value of 2.2 nM and a, submicromolar EC(50) in antiviral tests, showed no toxicity in tissue, culture, weakly inhibited human cathepsin D and pepsin, and was inactive, against trypsin, papain, and amylase. The structure of the parent cobalt, bis(1,2-dicarbollide) in complex with HIV PR was determined at 2.15 A, resolution by protein crystallography and represents the first, carborane-protein complex structure determined. It shows the following, mode of PR inhibition: two molecules of the parent compound bind to the, hydrophobic pockets in the flap-proximal region of the S3 and S3' subsites, of PR. We suggest, therefore, that these compounds block flap closure in, addition to filling the corresponding binding pockets as conventional PIs., This type of binding and inhibition, chemical and biological stability, low toxicity, and the possibility to introduce various modifications make, boron clusters attractive pharmacophores for potent and specific enzyme, inhibition.

About this Structure

1ZTZ is a Single protein structure of sequence from Human immunodeficiency virus 1 with CB5 as ligand. Active as HIV-1 retropepsin, with EC number 3.4.23.16 Full crystallographic information is available from OCA.

Reference

From nonpeptide toward noncarbon protease inhibitors: metallacarboranes as specific and potent inhibitors of HIV protease., Cigler P, Kozisek M, Rezacova P, Brynda J, Otwinowski Z, Pokorna J, Plesek J, Gruner B, Doleckova-Maresova L, Masa M, Sedlacek J, Bodem J, Krausslich HG, Kral V, Konvalinka J, Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15394-9. Epub 2005 Oct 14. PMID:16227435

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