High-resolution structure of a retroviral protease folded as a monomer.
Bottom Line: The flap has an unusual curled shape and a different orientation from both the open and closed states known from dimeric retropepsins.The overall fold of the protein follows the retropepsin canon, but the C(α) deviations are large and the active-site 'DTG' loop (here NTG) deviates up to 2.7 Å from the standard conformation.This structure of a monomeric retropepsin determined at high resolution (1.6 Å) provides important extra information for the design of dimerization inhibitors that might be developed as drugs for the treatment of retroviral infections, including AIDS.
Affiliation: Department of Crystallography, Faculty of Chemistry, A. Mickiewicz University, 60-780 Poznan, Poland.Show MeSH
Related in: MedlinePlus
Mentions: The flap of M-PMV PR (residues Ile45–Ser64; Fig. 2 ▶ b) has a peculiar shape. It is not a smooth hairpin with β-type interactions as in other retropepsins, but has a wide conformation with a 310-helical segment (Gln57–Asn59) present in its C-terminal part. The flap folds upon the body of the protein but in a way that is different from the ‘lowered’ flap position over the active site of retropepsin dimers in complex with inhibitors (Fig. 2 ▶ a). The flap arm appears to be much shorter because of the helical insertion and its blunt end. The leading/trailing strands follow the ‘lowered’/‘open’ flap traces of HIV-1 PR. The 310-helix in the trailing strand resembles a helical insertion in the flap of HTLV-1 (human T-cell leukaemia virus type-1) PR (Li et al., 2005 ▶).
Affiliation: Department of Crystallography, Faculty of Chemistry, A. Mickiewicz University, 60-780 Poznan, Poland.