Substitutions at the P2' site of gag p17-p24 affect cleavage efficiency by HIV-1 protease.
Heptapeptide substrates containing a single amino acid substitution at the p2' position of the gag p17-p24 junction (S-Q-N-Y-P-X-V where X = G, A, L, I, F, and W) were compared as substrates for HIV-1 protease. Binding of the Ile-, Leu-, and Ala- containing peptides was about equal although hydrolysis was 20-fold lower for the Ala and Leu peptides compared to Ile. Insertion of Gly or Phe at the p2' position resulted in significantly lower cleavage of the peptide while a Trp-containing peptide was not cleaved. These data suggest that a relatively small hydrophobic amino acid is important for hydrolysis and binding at this site. Structure-activity studies such as those described here may be useful in the design of specific inhibitors for HIV-1 protease.
Margolin
N
N
Molecular Biology Research, Lilly Research Laboratories, Indianapolis, IN 46285.
Heath
W
W
Osborne
E
E
Lai
M
M
Vlahos
C
C
D000595:Amino Acid Sequence; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D004926:Escherichia coli / Q000235:genetics; D015683:Gene Products, gag / Q000378:metabolism*; D015684:Gene Products, pol / Q000235:genetics / Q000378:metabolism*; D016333:HIV Protease; D015497:HIV-1 / Q000201:enzymology* / Q000235:genetics; D007700:Kinetics; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis; D011499:Protein Processing, Post-Translational; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity
D015683:Gene Products, gag; D015684:Gene Products, pol; D009842:Oligopeptides; D011994:Recombinant Proteins; D010450:Endopeptidases; D016333:HIV Protease