A phenylnorstatine inhibitor binding to HIV-1 protease: geometry, protonation, and subsite-pocket interactions analyzed at atomic resolution
Jazyk angličtina Země Spojené státy americké Médium print
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
15056001
DOI
10.1021/jm031105q
Knihovny.cz E-zdroje
- MeSH
- fenylbutyráty chemie MeSH
- HIV-proteasa chemie genetika MeSH
- inhibitory HIV-proteasy chemie MeSH
- krystalografie rentgenová MeSH
- molekulární modely MeSH
- mutace MeSH
- stereoizomerie MeSH
- termodynamika MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- virová léková rezistence genetika MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 3-amino-2-hydroxy-4-phenylbutanoic acid MeSH Prohlížeč
- fenylbutyráty MeSH
- HIV-proteasa MeSH
- inhibitory HIV-proteasy 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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