1t1f
From Proteopedia
(New page: 200px<br /> <applet load="1t1f" size="450" color="white" frame="true" align="right" spinBox="true" caption="1t1f, resolution 2.75Å" /> '''Crystal Structure o...) |
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| - | [[Image:1t1f.gif|left|200px]]<br /> | + | [[Image:1t1f.gif|left|200px]]<br /><applet load="1t1f" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1t1f" size=" | + | |
caption="1t1f, resolution 2.75Å" /> | caption="1t1f, resolution 2.75Å" /> | ||
'''Crystal Structure of Native Antithrombin in its Monomeric Form'''<br /> | '''Crystal Structure of Native Antithrombin in its Monomeric Form'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The poor inhibitory activity of circulating antithrombin (AT) is critical | + | The poor inhibitory activity of circulating antithrombin (AT) is critical to the formation of blood clots at sites of vascular damage. AT becomes an efficient inhibitor of the coagulation proteases only after binding to a specific heparin pentasaccharide, which alters the conformation of the reactive center loop (RCL). The molecular basis of this activation event lies at the heart of the regulation of hemostasis and accounts for the anticoagulant properties of the low molecular weight heparins. Although several structures of AT have been solved, the conformation of the RCL in native AT remains unknown because of the obligate crystal contact between the RCL of native AT and its latent counterpart. Here we report the crystallographic structure of a variant of AT in its monomeric native state. The RCL shifted approximately 20 A, and a salt bridge was observed between the P1 residue (Arg-393) and Glu-237. This contact explains the effect of mutations at the P1 position on the affinity of AT for heparin and also the properties of AT-Truro (E237K). The relevance of the observed conformation was verified through mutagenesis studies and by solving structures of the same variant in different crystal forms. We conclude that the poor inhibitory activity of the circulating form of AT is partially conferred by intramolecular contacts that restrain the RCL, orient the P1 residue away from attacking proteases, and additionally block the exosite utilized in protease recognition. |
==About this Structure== | ==About this Structure== | ||
| - | 1T1F is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with IOD and GOL as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | + | 1T1F is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=IOD:'>IOD</scene> and <scene name='pdbligand=GOL:'>GOL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1T1F OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Huntington, J | + | [[Category: Huntington, J A.]] |
| - | [[Category: Johnson, D | + | [[Category: Johnson, D J.D.]] |
[[Category: GOL]] | [[Category: GOL]] | ||
[[Category: IOD]] | [[Category: IOD]] | ||
[[Category: serine-cysteine proteinase inhibitor; thrombin; human; x-ray crystallography]] | [[Category: serine-cysteine proteinase inhibitor; thrombin; human; x-ray crystallography]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:08:50 2008'' |
Revision as of 13:08, 21 February 2008
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Crystal Structure of Native Antithrombin in its Monomeric Form
Overview
The poor inhibitory activity of circulating antithrombin (AT) is critical to the formation of blood clots at sites of vascular damage. AT becomes an efficient inhibitor of the coagulation proteases only after binding to a specific heparin pentasaccharide, which alters the conformation of the reactive center loop (RCL). The molecular basis of this activation event lies at the heart of the regulation of hemostasis and accounts for the anticoagulant properties of the low molecular weight heparins. Although several structures of AT have been solved, the conformation of the RCL in native AT remains unknown because of the obligate crystal contact between the RCL of native AT and its latent counterpart. Here we report the crystallographic structure of a variant of AT in its monomeric native state. The RCL shifted approximately 20 A, and a salt bridge was observed between the P1 residue (Arg-393) and Glu-237. This contact explains the effect of mutations at the P1 position on the affinity of AT for heparin and also the properties of AT-Truro (E237K). The relevance of the observed conformation was verified through mutagenesis studies and by solving structures of the same variant in different crystal forms. We conclude that the poor inhibitory activity of the circulating form of AT is partially conferred by intramolecular contacts that restrain the RCL, orient the P1 residue away from attacking proteases, and additionally block the exosite utilized in protease recognition.
About this Structure
1T1F is a Single protein structure of sequence from Homo sapiens with and as ligands. Full crystallographic information is available from OCA.
Reference
Crystal structure of monomeric native antithrombin reveals a novel reactive center loop conformation., Johnson DJ, Langdown J, Li W, Luis SA, Baglin TP, Huntington JA, J Biol Chem. 2006 Nov 17;281(46):35478-86. Epub 2006 Sep 13. PMID:16973611
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