CONSERVED MODE OF PEPTIDOMIMETIC INHIBITION AND SUBSTRATE RECOGNITIONOF HUMAN CYTOMEGALOVIRUS PROTEASE

Human cytomegalovirus (HCMV) protease belongs to a new class of serine proteases, with a unique polypeptide backbone fold. The crystal struc ture of the protease in complex with a peptidomimetic inhibitor (based on the natural substrates and covering the P-4 to P-1' positions) has been determined at 2.7 Angstrom resolution. The inhibitor is bound in an extended conformation, forming an anti-parallel beta-sheet with th e protease. The P-3 and P-1 side chains are less accessible to solvent , whereas the P-4 and P-2 side chains are more exposed. The inhibitor binding mode shows significant similarity to those observed for peptid omimetic inhibitors or substrates of other classes of serine proteases (chymotrypsin and subtilisin). HCMV protease therefore represents exa mple of convergent evolution. In addition, large conformational differ ences relative to the structure of the free enzyme are observed, which may be important for inhibitor binding.