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PDBsum entry 1irh
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Protein binding
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PDB id
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1irh
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Contents |
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* Residue conservation analysis
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DOI no:
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Biochemistry
41:78-85
(2002)
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PubMed id:
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Structural mechanism for heparin-binding of the third Kunitz domain of human tissue factor pathway inhibitor.
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S.Mine,
T.Yamazaki,
T.Miyata,
S.Hara,
H.Kato.
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ABSTRACT
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Tissue factor pathway inhibitor (TFPI) inhibits the activity of coagulation
factor VIIa and Xa through its K1 and K2 domain, respectively, and the
inhibitory activity is enhanced by heparin. The function of the K3 domain of
TFPI has not been established, but the domain probably harbors a heparin binding
site (HBS-2). We determined the three-dimensional solution structure of the TFPI
K3 domain (Glu182-Gly242) by heteronuclear multidimensional NMR. The results
showed that the molecule is composed of one antiparallel beta-sheet and one
alpha-helix, and in overall structure is very similar to the K2 domain, with the
rms deviation of 1.55 A for the 58 defined C(alpha) positions. However, the
surface electrostatic properties of both domains are different each other. The
lack of inhibitory activity of the K3 domain is explained by the absence of
electrostatic interaction with factor Xa over a large surface area. A titration
experiment with size-fractionated heparin showed that a heparin binding site was
located in the vicinity of the alpha-helix. In this region, a positively charged
cluster is formed by Lys213, Lys232, and Lys240, and the negatively charged
sulfate groups of heparin bind there. The enhancement of inhibitory activity by
heparin probably was not due to a conformational change to TFPI itself. It is
likely that heparin simply increases the local concentration of TFPI on the cell
surface and stabilizes the initial complex that forms.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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S.Macedo-Ribeiro,
C.Almeida,
B.M.Calisto,
T.Friedrich,
R.Mentele,
J.Stürzebecher,
P.Fuentes-Prior,
and
P.J.Pereira
(2008).
Isolation, cloning and structural characterisation of boophilin, a multifunctional Kunitz-type proteinase inhibitor from the cattle tick.
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PLoS ONE,
3,
e1624.
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PDB code:
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T.Hamuro,
H.Kido,
Y.Asada,
K.Hatakeyama,
Y.Okumura,
Y.Kunori,
T.Kamimura,
S.Iwanaga,
and
S.Kamei
(2007).
Tissue factor pathway inhibitor is highly susceptible to chymase-mediated proteolysis.
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FEBS J,
274,
3065-3077.
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E.P.Bianchini,
R.N.Pike,
and
B.F.Le Bonniec
(2004).
The elusive role of the potential factor X cation-binding exosite-1 in substrate and inhibitor interactions.
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J Biol Chem,
279,
3671-3679.
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N.Ohkura,
S.Hiraishi,
H.Itabe,
T.Hamuro,
Y.Kamikubo,
T.Takano,
J.Matsuda,
and
S.Horie
(2004).
Oxidized phospholipids in oxidized low-density lipoprotein reduce the activity of tissue factor pathway inhibitor through association with its carboxy-terminal region.
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Antioxid Redox Signal,
6,
705-712.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
code is
shown on the right.
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Links
