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| {{STRUCTURE_1rd3| PDB=1rd3 | SCENE= }} | | {{STRUCTURE_1rd3| PDB=1rd3 | SCENE= }} |
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| '''2.5A Structure of Anticoagulant Thrombin Variant E217K'''
| | ===2.5A Structure of Anticoagulant Thrombin Variant E217K=== |
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| ==Overview==
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| Thrombin is the ultimate protease of the blood clotting cascade and plays a major role in its own regulation. The ability of thrombin to exhibit both pro- and anti-coagulant properties has spawned efforts to turn thrombin into an anticoagulant for therapeutic purposes. This quest culminated in the identification of the E217K variant through scanning and saturation mutagenesis. The antithrombotic properties of E217K thrombin are derived from its inability to convert fibrinogen to a fibrin clot while maintaining its thrombomodulin-dependent ability to activate the anticoagulant protein C pathway. Here we describe the 2.5-A crystal structure of human E217K thrombin, which displays a dramatic restructuring of the geometry of the active site. Of particular interest is the repositioning of Glu-192, which hydrogen bonds to the catalytic Ser-195 and which results in the complete occlusion of the active site and the destruction of the oxyanion hole. Substrate binding pockets are further blocked by residues previously implicated in thrombin allostery. We have concluded that the E217K mutation causes the allosteric inactivation of thrombin by destabilizing the Na(+) binding site and that the structure thus may represent the Na(+)-free, catalytically inert "slow" form.
| | The line below this paragraph, {{ABSTRACT_PUBMED_15075325}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 15075325 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_15075325}} |
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| ==Disease== | | ==Disease== |
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| [[Category: Myles, T.]] | | [[Category: Myles, T.]] |
| [[Category: Hydrolase]] | | [[Category: Hydrolase]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 07:21:00 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 15:16:11 2008'' |