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PDBsum entry 2h9e
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Hydrolase/hydrolase inhibitor
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PDB id
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2h9e
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References listed in PDB file
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Key reference
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Title
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Intermolecular interactions and characterization of the novel factor xa exosite involved in macromolecular recognition and inhibition: crystal structure of human gla-Domainless factor xa complexed with the anticoagulant protein napc2 from the hematophagous nematode ancylostoma caninum.
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Authors
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M.T.Murakami,
J.Rios-Steiner,
S.E.Weaver,
A.Tulinsky,
J.H.Geiger,
R.K.Arni.
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Ref.
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J Mol Biol, 2007,
366,
602-610.
[DOI no: ]
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PubMed id
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Abstract
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NAPc2, an anticoagulant protein from the hematophagous nematode Ancylostoma
caninum evaluated in phase-II/IIa clinical trials, inhibits the extrinsic blood
coagulation pathway by a two step mechanism, initially interacting with the
hitherto uncharacterized factor Xa exosite involved in macromolecular
recognition and subsequently inhibiting factor VIIa (K(i)=8.4 pM) of the factor
VIIa/tissue factor complex. NAPc2 is highly flexible, becoming partially ordered
and undergoing significant structural changes in the C terminus upon binding to
the factor Xa exosite. In the crystal structure of the ternary factor
Xa/NAPc2/selectide complex, the binding interface consists of an intermolecular
antiparallel beta-sheet formed by the segment of the polypeptide chain
consisting of residues 74-80 of NAPc2 with the residues 86-93 of factor Xa that
is additional maintained by contacts between the short helical segment (residues
67-73) and a turn (residues 26-29) of NAPc2 with the short C-terminal helix of
factor Xa (residues 233-243). This exosite is physiologically highly relevant
for the recognition and inhibition of factor X/Xa by macromolecular substrates
and provides a structural motif for the development of a new class of inhibitors
for the treatment of deep vein thrombosis and angioplasty.
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Figure 2.
Figure 2. Overlays of the NAPc2 crystallographic structure
(red) on (a) the NMR-derived average structure (gray); and (b)
crystallographic structure of NAP5 (gray; J.R.S. and A.T.,
unpublished results). Figure 2. Overlays of the NAPc2
crystallographic structure (red) on (a) the NMR-derived average
structure (gray); and (b) crystallographic structure of NAP5
(gray; J.R.S. and A.T., unpublished results).
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Figure 3.
Figure 3. (a) Surface representation of the model of the
complex TF (green), fVIIa (catalytic domain in pink and EGF1,
EGF2 and Gla domains in yellow), fX (catalytic domain in gray
and EGF1, EGF2 and Gla domains in blue). NAPc2 is in red (ribbon
representation), yellow circle and arrow indicate the position
of the insertion-loop containing the P1 (Arg44) residue. (b)
Same as (a) but with the fXa re-positioned to permit the
simultaneous binding of NAPc2 to the fXa exosite and the fVIIa
active site. (c) Ribbon representation of the fXa-NAPc2 complex.
The yellow circle indicates the antiparallel β-strand
interactions between NAPc2 (red) and fXa (dark blue). (d)
Surface charge of fVIIa with the modeled peptide fragment of the
NAPc2 insertion-loop containing Arg44 in the active site
cavity. Figure 3. (a) Surface representation of the model of
the complex TF (green), fVIIa (catalytic domain in pink and
EGF1, EGF2 and Gla domains in yellow), fX (catalytic domain in
gray and EGF1, EGF2 and Gla domains in blue). NAPc2 is in red
(ribbon representation), yellow circle and arrow indicate the
position of the insertion-loop containing the P1 (Arg44)
residue. (b) Same as (a) but with the fXa re-positioned to
permit the simultaneous binding of NAPc2 to the fXa exosite and
the fVIIa active site. (c) Ribbon representation of the
fXa-NAPc2 complex. The yellow circle indicates the antiparallel
β-strand interactions between NAPc2 (red) and fXa (dark blue).
(d) Surface charge of fVIIa with the modeled peptide fragment of
the NAPc2 insertion-loop containing Arg44 in the active site
cavity.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2007,
366,
602-610)
copyright 2007.
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