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 active-site loop with the DTG (here NTG) triad has the general conformation as in other pepsins. However, in the absence of its replica, the key interactions (Oδ1⋯Wat⋯Oδ1, ‘fireman’s grip’) are missing and the side chains of Asn26 and Thr27 form only weak (∼3 Å) contacts with water molecules. On close comparison, the loop deviates significantly from the trace in HIV-1 PR (Fig. 3 ▶); the Cα deviations culminate (2.1 Å) at Asn26, with the departure of the Oδ1 atom being even larger (2.7 Å). This indicates that fine-tuning of the active-site geometry of retropepsins is only possible upon dimerization.
Affiliation: Department of Crystallography, Faculty of Chemistry, A. Mickiewicz University, 60-780 Poznan, Poland.