Comparative properties of feline immunodeficiency virus (FIV) and human immunodeficiency virus type 1 (HIV-1) proteinases prepared by total chemical synthesis.
The aspartyl proteinase (PR) encoded by the feline immunodeficiency virus (FIV) was prepared by total chemical synthesis. The 116-amino-acid polypeptide chain was assembled in a stepwise fashion using a Boc chemistry solid-phase peptide synthesis approach and subsequently folded into the biologically active dimeric proteinase. The synthetic enzyme showed proteolytic activity against a variety of different peptide substrates corresponding to putative cleavage sites of the Gag and Gag-Pol polyproteins of FIV. A comparative study with the proteinase of human immunodeficiency virus type 1 (HIV-1) showed that the FIV and HIV-1 enzymes have related but distinct substrate specificities. In particular, HIV-1 PR and FIV PR each show a strong preference for their own MA/CA substrates, despite identical amino acid residues at four of seven positions from P3-P4' of the substrate including an identical MA/CA cleavage site (between Tyr approximately Pro residues). FIV PR also showed a requirement for a longer peptide substrate than HIV-1 PR. Defining the similarities and the differences in the properties of these two retroviral enzymes will have a significant impact on structure-based drug design.
Schnölzer
M
M
Division of Cell Biology/0110, German Cancer Research Center, Heidelberg, Federal Republic of Germany.
Rackwitz
H R
HR
Gustchina
A
A
Laco
G S
GS
Wlodawer
A
A
Elder
J H
JH
Kent
S B
SB
D000595:Amino Acid Sequence; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000138:chemical synthesis* / Q000378:metabolism; D002415:Cats; D016333:HIV Protease / Q000138:chemical synthesis* / Q000378:metabolism; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D016089:Immunodeficiency Virus, Feline / Q000201:enzymology*; D008969:Molecular Sequence Data; D013379:Substrate Specificity
D016282:Aspartic Acid Endopeptidases; C095555:FIV protease; D016333:HIV Protease