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1tq0

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[[Image:1tq0.gif|left|200px]]
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{{STRUCTURE_1tq0| PDB=1tq0 | SCENE= }}
{{STRUCTURE_1tq0| PDB=1tq0 | SCENE= }}
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'''Crystal structure of the potent anticoagulant thrombin mutant W215A/E217A in free form'''
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===Crystal structure of the potent anticoagulant thrombin mutant W215A/E217A in free form===
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==Overview==
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The thrombin mutant W215A/E217A features a drastically impaired catalytic activity toward chromogenic and natural substrates but efficiently activates the anticoagulant protein C in the presence of thrombomodulin. As the remarkable anticoagulant properties of this mutant continue to be unraveled in preclinical studies, we solved the x-ray crystal structures of its free form and its complex with the active site inhibitor H-d-Phe-Pro-Arg-CH(2)Cl (PPACK). The PPACK-bound structure of W215A/E217A is identical to the structure of the PPACK-bound slow form of thrombin. On the other hand, the structure of the free form reveals a collapse of the 215-217 strand that crushes the primary specificity pocket. The collapse results from abrogation of the stacking interaction between Phe-227 and Trp-215 and the polar interactions of Glu-217 with Thr-172 and Lys-224. Other notable changes are a rotation of the carboxylate group of Asp-189, breakage of the H-bond between the catalytic residues Ser-195 and His-57, breakage of the ion pair between Asp-222 and Arg-187, and significant disorder in the 186- and 220-loops that define the Na(+) site. These findings explain the impaired catalytic activity of W215A/E217A and demonstrate that the analysis of the molecular basis of substrate recognition by thrombin and other proteases requires crystallization of both the free and bound forms of the enzyme.
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(as it appears on PubMed at http://www.pubmed.gov), where 15252033 is the PubMed ID number.
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{{ABSTRACT_PUBMED_15252033}}
==Disease==
==Disease==
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[[Category: Anticoagulant]]
[[Category: Anticoagulant]]
[[Category: Thrombin]]
[[Category: Thrombin]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 10:14:21 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 05:31:16 2008''

Revision as of 02:31, 28 July 2008

Image:1tq0.png

Template:STRUCTURE 1tq0

Contents

Crystal structure of the potent anticoagulant thrombin mutant W215A/E217A in free form

Template:ABSTRACT PUBMED 15252033

Disease

Known disease associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]

About this Structure

1TQ0 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.

Reference

The anticoagulant thrombin mutant W215A/E217A has a collapsed primary specificity pocket., Pineda AO, Chen ZW, Caccia S, Cantwell AM, Savvides SN, Waksman G, Mathews FS, Di Cera E, J Biol Chem. 2004 Sep 17;279(38):39824-8. Epub 2004 Jul 13. PMID:15252033

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