Article

X-ray analysis of HIV-1 proteinase at 2.7 Å resolution confirms structural homology among retroviral enzymes

Birkbeck, University of London, Londinium, England, United Kingdom
Nature (Impact Factor: 42.35). 12/1989; 342(6247):299-302. DOI: 10.1038/342299a0
Source: PubMed

ABSTRACT Knowledge of the tertiary structure of the proteinase from human immunodeficiency virus HIV-1 is important to the design of inhibitors that might possess antiviral activity and thus be useful in the treatment of AIDS. The conserved Asp-Thr/Ser-Gly sequence in retroviral proteinases suggests that they exist as dimers similar to the ancestor proposed for the pepsins. Although this has been confirmed by X-ray analyses of Rous sarcoma virus and HIV-1 proteinases, these structures have overall folds that are similar to each other only where they are also similar to the pepsins. We now report a further X-ray analysis of a recombinant HIV-1 proteinase at 2.7 A resolution. The polypeptide chain adopts a fold in which the N- and C-terminal strands are organized together in a four-stranded beta-sheet. A helix precedes the single C-terminal strand, as in the Rous sarcoma virus proteinase and also in a synthetic HIV-1 proteinase, in which the cysteines have been replaced by alpha-aminobuytric acid. The structure reported here provides an explanation for the amino acid invariance amongst retroviral proteinases, but differs from that reported earlier in some residues that are candidates for substrate interactions at P3, and in the mode of intramolecular cleavage during processing of the polyprotein.

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    • "The major substrate specificity signature features of HIV PR involve (i) a preference for Glu in the P2 0 position; (ii) a certain preference for large aliphatic and Fig. 2. Three-dimensional structures of selected retroviral PRs. (A) Crystal structures of HIV-1 PR in three conformations: the apo-form of the HIV-1 PR with flaps in open conformation (PDB code 3PHV (Lapatto et al., 1989)), HIV-1 PR with flaps in closed conformation (PDB code 4LL3 (Kozisek et al., 2014)) with inhibitor (DRV) bound in the enzyme active site shown in sticks (with carbon atoms colored green, oxygen atoms red, nitrogens blue and sulfur yellow), HIV-1 PR with flaps in semi-open conformation (PDB code 1ZTZ (Cigler et al., 2005). Inhibitor bound in the enzyme active site (metallacarborane) is shown in sticks (with carbon atoms colored yellow, boron atoms cyan, and cobalt atom maroon). "
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    Virology 03/2015; 479-480. DOI:10.1016/j.virol.2015.03.021 · 3.28 Impact Factor
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    • "The flexibility and the flap switch in the active site on some aspartic proteases (e.g. HIV-1 protease, renin, BACE1 and plasmepsin II) upon ligands/inhibitors binding were analysed by several experimental and computational studies (Hong & Tang, 2004; Hornak, Okur, Rizzo & Simmerling, 2006; Lapatto et al., 1989; Pietrucci, Marinelli, Carloni, & Laio, 2009; Politi et al., 2011; Sadiq & De Fabritiis, 2010; Steiner et al., 2011; Tzoupis et al., 2012; Xu et al., 2012). Specific MD simulations on HIV-1 protease reveal a reversible transition between open and closed flap conformations (Shang & Simmerling, 2012). "
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    • "In contrast, retroviral PRs only contain one Asp-Thr-Gly motif and must therefore form a true dimer. Indeed X-ray crystallography has shown that the HIV-1 PR exists as a dimer consisting of two identical monomers [19] [20] [21]. The crystal structure of the dimer reveals that four-stranded β sheets derived from both ends of each monomer hold the dimer together. "
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