1oyh
From Proteopedia
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| - | + | {{STRUCTURE_1oyh| PDB=1oyh | SCENE= }} | |
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'''Crystal Structure of P13 Alanine Variant of Antithrombin''' | '''Crystal Structure of P13 Alanine Variant of Antithrombin''' | ||
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[[Category: Huntington, J A.]] | [[Category: Huntington, J A.]] | ||
[[Category: Johnson, D J.D.]] | [[Category: Johnson, D J.D.]] | ||
| - | [[Category: | + | [[Category: Heparin analogue]] |
| - | [[Category: | + | [[Category: Inhibition]] |
| - | [[Category: | + | [[Category: Serine protease inhibitor]] |
| - | [[Category: | + | [[Category: Thrombin]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 04:26:08 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 01:26, 3 May 2008
Crystal Structure of P13 Alanine Variant of Antithrombin
Overview
Antithrombin becomes an efficient inhibitor of factor Xa and thrombin by binding a specific pentasaccharide sequence found on a small fraction of the heparan sulfate proteoglycans lining the microvaculature. In the structure of native antithrombin, the reactive center loop is restrained due to the insertion of its hinge region into the main beta-sheet A, whereas in the heparin-activated state the reactive center loop is freed from beta-sheet A. In both structures, hinge region residue Glu-381 makes several stabilizing contacts. To determine the role of these contacts in the allosteric mechanism of antithrombin activation, we replaced Glu-381 with an alanine. This variant is less active toward its target proteases than control antithrombin, due to a perturbation of the equilibrium between the two forms, and to an increase in stoichiometry of inhibition. Pentasaccharide binding affinity is reduced 4-fold due to an increase in the off-rate. These data suggest that the main role of Glu-381 is to stabilize the activated conformation. Stability studies also showed that the E381A variant is resistant to continued insertion of its reactive center loop upon incubation at 50 degrees C, suggesting new stabilizing interactions in the native structure. To test this hypothesis, and to aid in the interpretation of the kinetic data we solved to 2.6 A the structure of the variant. We conclude that wild-type Glu-381 interactions stabilize the activated state and decreases the energy barrier to full loop insertion.
About this Structure
1OYH is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
Reference
The influence of hinge region residue Glu-381 on antithrombin allostery and metastability., Johnson DJ, Huntington JA, J Biol Chem. 2004 Feb 6;279(6):4913-21. Epub 2003 Nov 17. PMID:14623882 Page seeded by OCA on Sat May 3 04:26:08 2008
