Biophys J, March 2002, p. 1190-1206, Vol. 82, No. 3

Structure and Dynamics of Zymogen Human Blood Coagulation Factor X

Divi Venkateswarlu,^* Lalith Perera,^* Tom Darden, and Lee G. Pedersen^*

 ^*Department of Chemistry, Venable Hall, University of North Carolina, Chapel Hill, North Carolina 27599, and  National Institute of Environment Health Science, Research Triangle Park, North Carolina 27709 USA

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-Å-resolution x-ray crystallographic structure of active-site inhibited human FXa (PDB:1XKA). The missing -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 ~95 Å in contrast to ~83 Å 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.

Biophys J, March 2002, p. 1190-1206, Vol. 82, No. 3
© 2002 by the Biophysical Society   0006-3495/02/03/1190/17  $2.00

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