title: Computational study of the putative active form of protein Z (PZa): sequence design and structural modeling.
abstract: Although protein Z (PZ) has a domain arrangement similar to the essential coagulation proteins FVII, FIX, FX, and protein C, its serine protease (SP)-like domain is incomplete and does not exhibit proteolytic activity. We have generated a trial sequence of putative activated protein Z (PZa) by identifying amino acid mutations in the SP-like domain that might reasonably resurrect the serine protease catalytic activity of PZ. The structure of the activated form was then modeled based on the proposed sequence using homology modeling and solvent-equilibrated molecular dynamics simulations. In silico docking of inhibitors of FVIIa and FXa to the putative active site of equilibrated PZa, along with structural comparison with its homologous proteins, suggest that the designed PZa can possibly act as a serine protease.
authors.affiliation: Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Vasu
authors.initials: V
authors.lastname: Chandrasekaran
authors.forename: Chang Jun
authors.initials: CJ
authors.lastname: Lee
authors.forename: Robert E
authors.initials: RE
authors.lastname: Duke
authors.forename: Lalith
authors.initials: L
authors.lastname: Perera
authors.forename: Lee G
authors.initials: LG
authors.lastname: Pedersen
mesh_terms: D000595:Amino Acid Sequence; D001798:Blood Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D020134:Catalytic Domain; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D015942:Factor VIIa / Q000737:chemistry / Q000378:metabolism; D015951:Factor Xa / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000187:drug effects; D011486:Protein C / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship
chemical_list: D001798:Blood Proteins; D011486:Protein C; D015842:Serine Proteinase Inhibitors; C026080:plasma protein Z; D015942:Factor VIIa; D015951:Factor Xa