title: Structure and dynamics of zymogen human blood coagulation factor X.
abstract: The solution structure and dynamics of the human coagulation factor X (FX) have been investigated to understand the key structural elements in the zymogenic form that participates in the activation process. The model was constructed based on the 2.3-A-resolution x-ray crystallographic structure of active-site inhibited human FXa (PDB:1XKA). The missing gamma-carboxyglutamic acid (GLA) and part of epidermal growth factor 1 (EGF1) domains of the light chain were modeled based on the template of GLA-EGF1 domains of the tissue factor (TF)-bound FVIIa structure (PDB:1DAN). The activation peptide and other missing segments of FX were introduced using homology modeling. The full calcium-bound model of FX was subjected to 6.2 ns of molecular dynamics simulation in aqueous medium using the AMBER6.0 package. We observed significant reorientation of the serine-protease (SP) domain upon activation leading to a compact multi-domain structure. The solution structure of zymogen appears to be in a well-extended conformation with the distance between the calcium ions in the GLA domain and the catalytic residues estimated to be approximately 95 A in contrast to approximately 83 A in the activated form. The latter is in close agreement with fluorescence studies on FXa. The S1-specificity residues near the catalytic triad show significant differences between the zymogen and activated structures.
authors.affiliation: Department of Chemistry, Venable Hall, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Divi
authors.initials: D
authors.lastname: Venkateswarlu
authors.forename: Lalith
authors.initials: L
authors.lastname: Perera
authors.forename: Tom
authors.initials: T
authors.lastname: Darden
authors.forename: Lee G
authors.initials: LG
authors.lastname: Pedersen
mesh_terms: D015055:1-Carboxyglutamic Acid / Q000737:chemistry; D000595:Amino Acid Sequence; D001665:Binding Sites; D001779:Blood Coagulation Factors / Q000737:chemistry*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004792:Enzyme Precursors / Q000097:blood* / Q000737:chemistry* / Q000235:genetics; D004815:Epidermal Growth Factor / Q000737:chemistry; D005170:Factor X / Q000737:chemistry* / Q000235:genetics; D015951:Factor Xa / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D012697:Serine Endopeptidases / Q000378:metabolism
chemical_list: D001779:Blood Coagulation Factors; D004792:Enzyme Precursors; D015055:1-Carboxyglutamic Acid; D004815:Epidermal Growth Factor; D005170:Factor X; D012697:Serine Endopeptidases; D015951:Factor Xa