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

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 AIDS¹. The conserved Asp–Thr/Ser–Gly sequence in retroviral proteinases² suggests that they exist as dimers similar to the ancestor proposed for the pepsins^3–5. Although this has been confirmed by X-ray analyses of Rous sarcoma virus and HIV-1 proteinases^6,7, these structures have overall folds that are similar to each other only where they are also similar to the pepsins⁸. We now report a further X-ray analysis of a recombinant HIV-1 proteinase at 2.7 Å resolution. The polypeptide chain adopts a fold in which the N- and C-terminal strands are organized together in a four-stranded β-sheet. A helix precedes the single C-terminal strand, as in the Rous sarcoma virus proteinase⁶ and also in a synthetic HIV-1 proteinase, in which the cysteines have been replaced by α-aminobutyric acid⁹. The structure reported here provides an explanation for the amino acid invariance amongst retroviral proteinases, but differs from that reported earlier⁷ in some residues that are candidates for substrate interactions at P₃, and in the mode of intramolecular cleavage during processing of the polyprotein.