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Biophys J, December 2000, p. 2925-2943, Vol. 79, No. 6
*Department of Chemistry, University of North Carolina, Chapel
Hill, North Carolina 27599-3290; National Institute of
Environment Health Science, Research Triangle Park, North Carolina
27709; Department of Biology, University of North
Carolina, Chapel Hill, North Carolina 27599-3290; §Howard
Hughes Medical Institute, Oklahoma Medical Research Foundation, 825 NE13, Oklahoma City, Oklahoma 73104 USA
A solution structure for the complete zymogen form of
human coagulation protein C is modeled. The initial core structure is based on the x-ray crystallographic structure of the
-carboxyglutamic acid (Gla)-domainless activated form. The Gla
domain (residues 1-48) is modeled from the x-ray crystal coordinates
of the factor VIIa/tissue factor complex and oriented with
the epidermal growth factor-1 domain to yield an initial orientation
consistent with the x-ray crystal structure of porcine factor
IXa. The missing C-terminal residues in the light chain
(residues 147-157) and the activation peptide residues 158-169 were
introduced using homology modeling so that the activation peptide
residues directly interact with the residues in the calcium binding
loop. Molecular dynamics simulations (Amber-particle-mesh-Ewald) are
used to obtain the complete calcium-complexed solution structure. The
individual domain structures of protein C in solution are largely
unaffected by solvation, whereas the Gla-epidermal growth factor-1
orientation evolves to a form different from both factors
VIIa and IXa. The solution structure of the
zymogen protein C is compared with the crystal structures of the
existing zymogen serine proteases: chymotrypsinogen, proproteinase, and
prethrombin-2. Calculated electrostatic potential surfaces support the
involvement of the serine protease calcium ion binding loop in
providing a suitable electrostatic environment around the scissile bond
for IIa/thrombomodulin interaction.
Biophys J, December 2000, p. 2925-2943, Vol. 79, No. 6
© 2000 by the Biophysical Society 0006-3495/00/12/2925/19 $2.00
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