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PDBsum entry 2p3f
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References listed in PDB file
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Key reference
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Title
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Active and exo-Site inhibition of human factor xa: structure of des-Gla factor xa inhibited by nap5, A potent nematode anticoagulant protein from ancylostoma caninum.
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Authors
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J.L.Rios-Steiner,
M.T.Murakami,
A.Tulinsky,
R.K.Arni.
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Ref.
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J Mol Biol, 2007,
371,
774-786.
[DOI no: ]
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PubMed id
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Abstract
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Hookworms are hematophagous nematodes capable of growth, development and
subsistence in living host systems such as humans and other mammals.
Approximately one billion, or one in six, people worldwide are infected by
hookworms causing gastrointestinal blood loss and iron deficiency anemia. The
hematophagous hookworm Ancylostoma caninum produces a family of small,
disulfide-linked protein anticoagulants (75-84 amino acid residues). One of
these nematode anticoagulant proteins, NAP5, inhibits the amidolytic activity of
factor Xa (fXa) with K(i)=43 pM, and is the most potent natural fXa inhibitor
identified thus far. The crystal structure of NAP5 bound at the active site of
gamma-carboxyglutamic acid domainless factor Xa (des-fXa) has been determined at
3.1 A resolution, which indicates that Asp189 (fXa, S1 subsite) binds to Arg40
(NAP5, P1 site) in a mode similar to that of the BPTI/trypsin interaction.
However, the hydroxyl group of Ser39 of NAP5 additionally forms a hydrogen bond
(2.5 A) with His57 NE2 of the catalytic triad, replacing the hydrogen bond of
Ser195 OG to the latter in the native structure, resulting in an interaction
that has not been observed before. Furthermore, the C-terminal extension of NAP5
surprisingly interacts with the fXa exosite of a symmetry-equivalent molecule
forming a short intermolecular beta-strand as observed in the structure of the
NAPc2/fXa complex. This indicates that NAP5 can bind to fXa at the active site,
or the exosite, and to fX at the exosite. However, unlike NAPc2, NAP5 does not
inhibit fVIIa of the fVIIa/TF complex.
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Figure 1.
Figure 1. Alignment of amino acid sequences of NAP5, NAP6 and
NAPc2. Differences from NAP5 are in bold; disulfide bonds are
shown as black lines; the conserved motif involved in exosite
binding id boxed in dark gray; non-conserved motifs involved in
the exosite binding boxed are in light gray; the NAP5 sequence
is numbered consecutively.
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Figure 2.
Figure 2. Stereoview of the superpositioning of C/E-1 on
NAP5. A ribbon representation of NAP5 is in blue, the NAP5
disulfide bridges are numbered, reactive-site P1 residues are
shown as yellow sticks (Arg40, NAP5; Leu31, C/E-1).
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2007,
371,
774-786)
copyright 2007.
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