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PDBsum entry 1e04
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Blood clotting
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PDB id
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1e04
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Contents |
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* Residue conservation analysis
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J Mol Biol
326:823-833
(2003)
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PubMed id:
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Structure of beta-antithrombin and the effect of glycosylation on antithrombin's heparin affinity and activity.
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A.J.McCoy,
X.Y.Pei,
R.Skinner,
J.P.Abrahams,
R.W.Carrell.
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ABSTRACT
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Antithrombin is a member of the serpin family of protease inhibitors and the
major inhibitor of the blood coagulation cascade. It is unique amongst the
serpins in that it circulates in a conformation that is inactive against its
target proteases. Activation of antithrombin is brought about by a
conformational change initiated upon binding heparin or heparan sulphate. Two
isoforms exist in the circulation, alpha-antithrombin and beta-antithrombin,
which differ in the amount of glycosylation present on the polypeptide chain;
beta-antithrombin lacks the carbohydrate present at Asn135 in
alpha-antithrombin. Of the two forms, beta-antithrombin has the higher affinity
for heparin and thus functions as the major inhibitor in vivo even though it is
the less abundant form. The reason for the differences in heparin affinity
between the alpha and beta-forms have been shown to be due to the additional
carbohydrate changing the rate of the conformational change. Here, we describe
the most accurate structures of alpha-antithrombin and
alpha-antithrombin+heparin pentasaccharide reported to date (2.6A and 2.9A
resolution, respectively, both re-refinements using old data), and the structure
of beta-antithrombin (2.6A resolution). The new structures have a remarkable
degree of ordered carbohydrate and include parts of the antithrombin chain not
modeled before. The structures have allowed a detailed comparison of the
conformational differences between the three. They show that the structural
basis of the lower affinity for heparin of alpha-antithrombin over
beta-antithrombin is due to the conformational change that occurs upon heparin
binding being sterically hindered by the presence of the additional bulky
carbohydrate at Asn135.
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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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C.An,
S.Lovell,
M.R.Kanost,
K.P.Battaile,
and
K.Michel
(2011).
Crystal structure of native Anopheles gambiae serpin-2, a negative regulator of melanization in mosquitoes.
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Proteins,
79,
1999-2003.
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PDB code:
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I.Martínez-Martínez,
A.Ordóñez,
J.Navarro-Fernández,
A.Pérez-Lara,
R.Gutiérrez-Gallego,
R.Giraldo,
C.Martínez,
E.Llop,
V.Vicente,
and
J.Corral
(2010).
Antithrombin Murcia (K241E) causing antithrombin deficiency: a possible role for altered glycosylation.
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Haematologica,
95,
1358-1365.
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Y.Chen,
W.Tan,
S.Qin,
J.Zhang,
H.Bu,
Y.Li,
Y.Lu,
and
J.Cheng
(2009).
Cloning of the full-length cDNA of porcine antithrombin III and comparison with its human homolog.
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Comp Med,
59,
372-377.
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S.Amon,
A.D.Zamfir,
and
A.Rizzi
(2008).
Glycosylation analysis of glycoproteins and proteoglycans using capillary electrophoresis-mass spectrometry strategies.
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Electrophoresis,
29,
2485-2507.
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E.Seyrek,
P.L.Dubin,
and
J.Henriksen
(2007).
Nonspecific electrostatic binding characteristics of the heparin-antithrombin interaction.
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Biopolymers,
86,
249-259.
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J.C.Rau,
L.M.Beaulieu,
J.A.Huntington,
and
F.C.Church
(2007).
Serpins in thrombosis, hemostasis and fibrinolysis.
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J Thromb Haemost,
5,
102-115.
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M.A.Klieber,
C.Underhill,
G.L.Hammond,
and
Y.A.Muller
(2007).
Corticosteroid-binding globulin, a structural basis for steroid transport and proteinase-triggered release.
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J Biol Chem,
282,
29594-29603.
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PDB codes:
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D.J.Johnson,
J.Langdown,
W.Li,
S.A.Luis,
T.P.Baglin,
and
J.A.Huntington
(2006).
Crystal structure of monomeric native antithrombin reveals a novel reactive center loop conformation.
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J Biol Chem,
281,
35478-35486.
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PDB codes:
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D.J.Johnson,
W.Li,
T.E.Adams,
and
J.A.Huntington
(2006).
Antithrombin-S195A factor Xa-heparin structure reveals the allosteric mechanism of antithrombin activation.
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EMBO J,
25,
2029-2037.
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PDB code:
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J.A.Huntington
(2006).
Shape-shifting serpins--advantages of a mobile mechanism.
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Trends Biochem Sci,
31,
427-435.
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A.Plematl,
U.M.Demelbauer,
D.Josic,
and
A.Rizzi
(2005).
Determination of the site-specific and isoform-specific glycosylation in human plasma-derived antithrombin by IEF and capillary HPLC-ESI-MS/MS.
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Proteomics,
5,
4025-4033.
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D.J.Johnson,
and
J.A.Huntington
(2004).
The influence of hinge region residue Glu-381 on antithrombin allostery and metastability.
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J Biol Chem,
279,
4913-4921.
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PDB code:
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U.R.Desai
(2004).
New antithrombin-based anticoagulants.
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Med Res Rev,
24,
151-181.
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G.Izaguirre,
W.Zhang,
R.Swanson,
T.Bedsted,
and
S.T.Olson
(2003).
Localization of an antithrombin exosite that promotes rapid inhibition of factors Xa and IXa dependent on heparin activation of the serpin.
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J Biol Chem,
278,
51433-51440.
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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
