A phenylnorstatine inhibitor binding to HIV-1 protease: geometry, protonation, and subsite-pocket interactions analyzed at atomic resolution
Language English Country United States Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
15056001
DOI
10.1021/jm031105q
Knihovny.cz E-resources
- MeSH
- Phenylbutyrates chemistry MeSH
- HIV Protease chemistry genetics MeSH
- HIV Protease Inhibitors chemistry MeSH
- Crystallography, X-Ray MeSH
- Models, Molecular MeSH
- Mutation MeSH
- Stereoisomerism MeSH
- Thermodynamics MeSH
- Protein Binding MeSH
- Binding Sites MeSH
- Drug Resistance, Viral genetics MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 3-amino-2-hydroxy-4-phenylbutanoic acid MeSH Browser
- Phenylbutyrates MeSH
- HIV Protease MeSH
- HIV Protease Inhibitors MeSH
The X-ray structure of a complex of HIV-1 protease (PR) with a phenylnorstatine inhibitor Z-Pns-Phe-Glu-Glu-NH(2) has been determined at 1.03 A, the highest resolution so far reported for any HIV PR complex. The inhibitor shows subnanomolar K(i) values for both the wild-type PR and the variant representing one of the most common mutations linked to resistance development. The structure comprising the phenylnorstatine moiety of (2R,3S)-chirality displays a unique pattern of hydrogen bonding to the two catalytic aspartate residues. This high resolution makes it possible to assess the donor and acceptor relations of this hydrogen bonding and to indicate a proton shared by the two catalytic residues. A structural mechanism for the unimpaired inhibition of the protease Val82Ala mutant is also suggested, based on energy calculations and analyses.
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