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: Despite its use during crystallization, the inhibitor is not present in the crystal structure and the protein exists in a monomeric fold. There are two independent 13PR molecules (A and B) in the asymmetric unit. They are virtually identical (Cα r.m.s.d. of 0.18 Å) and have the general chain topology known from the structures of dimeric retropepsins (Miller et al., 1989 ▶; Wlodawer et al., 1989 ▶). The polypeptide chains have excellent electron density for all structural elements, except for the N-terminus (residues 1–8) and C-terminus (104–114). The residues forming the flap loops show increased mobility (especially at the tips; Gln57–Ser58), which is visible as higher B factors, but there is no ambiguity about the tracing of these loops (Fig. 1 ▶) and their identical conformation in both molecules.
Affiliation: Department of Crystallography, Faculty of Chemistry, A. Mickiewicz University, 60-780 Poznan, Poland.