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| - | [[Image:1shh.gif|left|200px]] | + | {{Seed}} |
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| | {{STRUCTURE_1shh| PDB=1shh | SCENE= }} | | {{STRUCTURE_1shh| PDB=1shh | SCENE= }} |
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| - | '''Slow form of Thrombin Bound with PPACK'''
| + | ===Slow form of Thrombin Bound with PPACK=== |
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| - | ==Overview==
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| - | Na(+) binding near the primary specificity pocket of thrombin promotes the procoagulant, prothrombotic, and signaling functions of the enzyme. The effect is mediated allosterically by a communication between the Na(+) site and regions involved in substrate recognition. Using a panel of 78 Ala mutants of thrombin, we have mapped the allosteric core of residues that are energetically linked to Na(+) binding. These residues are Asp-189, Glu-217, Asp-222, and Tyr-225, all in close proximity to the bound Na(+). Among these residues, Asp-189 shares with Asp-221 the important function of transducing Na(+) binding into enhanced catalytic activity. None of the residues of exosite I, exosite II, or the 60-loop plays a significant role in Na(+) binding and allosteric transduction. X-ray crystal structures of the Na(+)-free (slow) and Na(+)-bound (fast) forms of thrombin, free or bound to the active site inhibitor H-d-Phe-Pro-Arg-chloromethyl-ketone, document the conformational changes induced by Na(+) binding. The slow --> fast transition results in formation of the Arg-187:Asp-222 ion pair, optimal orientation of Asp-189 and Ser-195 for substrate binding, and a significant shift of the side chain of Glu-192 linked to a rearrangement of the network of water molecules that connect the bound Na(+) to Ser-195 in the active site. The changes in the water network and the allosteric core explain the thermodynamic signatures linked to Na(+) binding and the mechanism of thrombin activation by Na(+). The role of the water network uncovered in this study establishes a new paradigm for the allosteric regulation of thrombin and other Na(+)-activated enzymes involved in blood coagulation and the immune response.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_15152000}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 15152000 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_15152000}} |
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| | ==Disease== | | ==Disease== |
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| | [[Category: Prasad, S.]] | | [[Category: Prasad, S.]] |
| | [[Category: Serine protease]] | | [[Category: Serine protease]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 08:42:39 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 23:34:07 2008'' |
Revision as of 20:34, 27 July 2008
Template:STRUCTURE 1shh
Slow form of Thrombin Bound with PPACK
Template:ABSTRACT PUBMED 15152000
Disease
Known disease associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]
About this Structure
1SHH is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Molecular dissection of Na+ binding to thrombin., Pineda AO, Carrell CJ, Bush LA, Prasad S, Caccia S, Chen ZW, Mathews FS, Di Cera E, J Biol Chem. 2004 Jul 23;279(30):31842-53. Epub 2004 May 19. PMID:15152000
Page seeded by OCA on Sun Jul 27 23:34:07 2008
