title: Conserved mode of peptidomimetic inhibition and substrate recognition of human cytomegalovirus protease.
abstract: 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 P4 to P1' positions) has been determined at 2.7 A resolution. The inhibitor is bound in an extended conformation, forming an anti-parallel beta-sheet with the protease. The P3 and P1 side chains are less accessible to solvent, whereas the P4 and P2 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.
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877, USA. tong@como.bio.columbia.edu
authors.forename: L
authors.initials: L
authors.lastname: Tong
authors.forename: C
authors.initials: C
authors.lastname: Qian
authors.forename: M J
authors.initials: MJ
authors.lastname: Massariol
authors.forename: R
authors.initials: R
authors.lastname: Déziel
authors.forename: C
authors.initials: C
authors.lastname: Yoakim
authors.forename: L
authors.initials: L
authors.lastname: Lagacé
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003587:Cytomegalovirus / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D046911:Macromolecular Substances; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D011480:Protease Inhibitors / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D055672:Static Electricity; D013379:Substrate Specificity
chemical_list: D046911:Macromolecular Substances; D009842:Oligopeptides; D011480:Protease Inhibitors; D012697:Serine Endopeptidases; C071910:assemblin