Conserved mode of peptidomimetic inhibition and substrate recognition of human cytomegalovirus protease

Human cytomegalovirus (HCMV) protease belongs to a new class of serine proteases, with a unique polypeptide backbone fold. The crystal structure 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 the 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 peptidomimetic inhibitors or substrates of other classes of serine proteases (chymotrypsin and subtilisin). HCMV protease therefore represents example of convergent evolution. In addition, large conformational differences relative to the structure of the free enzyme are observed, which may be important for inhibitor binding.