[Mechanism of aspartyl proteinase action. VII. Noncovalent complexes of HIV-1 aspartyl proteinase with substrate and substrate-like inhibitors]

Important note: Information in this article was accurate in 2000. The state of the art may have changed since the publication date.

[Mechanism of aspartyl proteinase action. VII. Noncovalent complexes of HIV-1 aspartyl proteinase with substrate and substrate-like inhibitors]

Bioorg Khim. 1999 Dec;25(12):911-22. Unique Identifier : AIDSLINE MED/20198726
Popov ME; Kashparov IV; Rumsh LD; Popov EM; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian; Academy of Sciences, Moscow, Russia. popov@enzyme.siobc.ras.ru

Abstract: A computer model of a noncovalent complex of HIV-1 aspartyl protease with substrate-like inhibitor JG-365 was a priori constructed by using the approaches of theoretical conformational analysis and molecular mechanics. The root mean square deviation of the calculated conformation of the inhibitor from the X-ray diffraction analysis data was 0.87 A. These results enabled the a priori calculation of the structure of noncovalent complex of HIV-1 protease with a hexapeptide fragment of its native specific substrate Ser-Gln-Asn-Tyr-Pro-Ile-Val. The only possible orientation of the cleavable peptide bond in this and the nucleophilic water molecule relative to the catalytically active Asp residues of the enzyme (Asp25 and Asp125) was found that provides for the chemical transformation of the substrate to a tetrahedral intermediate. An action mechanism of enzymes of this class was proposed on the basis of the analysis of calculated distances. We showed that neither steric distortion of the cleavable bond nor the formation of unfavorable contacts in molecules of the enzymes and their substrates accompany the optimum orientation of substrate molecules at the active sites of HIV-1 aspartyl proteases and rhizopuspepsin.

Keywords: JOURNAL ARTICLE kompleksy aspartil'noi proteinazy HIV-1 s substratom i substratopodobnym ingibitorom. English Abstract HIV Protease/*CHEMISTRY HIV Protease Inhibitors/*CHEMISTRY HIV-1/*CHEMISTRY Models, Molecular Molecular Conformation Oligopeptides/*CHEMISTRY
000730
A0071284

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