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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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References listed in PDB file
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Key reference
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Title
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Structure of beta-Antithrombin and the effect of glycosylation on antithrombin'S heparin affinity and activity.
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Authors
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A.J.Mccoy,
X.Y.Pei,
R.Skinner,
J.P.Abrahams,
R.W.Carrell.
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Ref.
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J Mol Biol, 2003,
326,
823-833.
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PubMed id
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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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