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
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Mentions: When the present M-PMV PR molecule is viewed from the direction of its absent dimerization partner, one sees a uniformly positively charged surface (Fig. 4 ▶). This is different from a similar view of the HIV-1 PR protomer, in which both charges and hydrophobic patches are seen, and may partly explain why in the absence of substrate/inhibitor the M-PMV protein can stably exist as a monomer, at least with the D26N mutation. Fig. 4 ▶ also illustrates that the curled flap closely covers the active-site cavity, while in the HIV-1 PR protomer extracted from the dimeric enzyme the cavity would be freely accessible.
Affiliation: Department of Crystallography, Faculty of Chemistry, A. Mickiewicz University, 60-780 Poznan, Poland.