3bei

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[[Image:3bei.jpg|left|200px]]
[[Image:3bei.jpg|left|200px]]
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{{Structure
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<!--
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|PDB= 3bei |SIZE=350|CAPTION= <scene name='initialview01'>3bei</scene>, resolution 1.55&Aring;
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The line below this paragraph, containing "STRUCTURE_3bei", creates the "Structure Box" on the page.
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|SITE= <scene name='pdbsite=AC1:Nag+Binding+Site+For+Residue+B+303'>AC1</scene>, <scene name='pdbsite=AC2:Gol+Binding+Site+For+Residue+B+301'>AC2</scene> and <scene name='pdbsite=AC3:Gol+Binding+Site+For+Residue+B+302'>AC3</scene>
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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|LIGAND= <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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|ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Thrombin Thrombin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.5 3.4.21.5] </span>
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or leave the SCENE parameter empty for the default display.
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|GENE= F2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
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-->
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|DOMAIN=
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{{STRUCTURE_3bei| PDB=3bei | SCENE= }}
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|RELATEDENTRY=[[3bef|3BEF]], [[2gp9|2GP9]]
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3bei FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3bei OCA], [http://www.ebi.ac.uk/pdbsum/3bei PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=3bei RCSB]</span>
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}}
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'''Crystal structure of the slow form of thrombin in a self_inhibited conformation'''
'''Crystal structure of the slow form of thrombin in a self_inhibited conformation'''
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==Overview==
==Overview==
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The activating effect of Na(+) on thrombin is allosteric and depends on the conformational transition from a low activity Na(+)-free (slow) form to a high activity Na(+)-bound (fast) form. The structures of these active forms have been solved. Recent structures of thrombin obtained in the absence of Na(+) have also documented inactive conformations that presumably exist in equilibrium with the active slow form. The validity of these inactive slow form structures, however, is called into question by the presence of packing interactions involving the Na(+) site and the active site regions. Here, we report a 1.87A resolution structure of thrombin in the absence of inhibitors and salts with a single molecule in the asymmetric unit and devoid of significant packing interactions in regions involved in the allosteric slow --&gt; fast transition. The structure shows an unprecedented self-inhibited conformation where Trp-215 and Arg-221a relocate &gt;10A to occlude the active site and the primary specificity pocket, and the guanidinium group of Arg-187 penetrates the protein core to fill the empty Na(+)-binding site. The extreme mobility of Trp-215 was investigated further with the W215P mutation. Remarkably, the mutation significantly compromises cleavage of the anticoagulant protein C but has no effect on the hydrolysis of fibrinogen and PAR1. These findings demonstrate that thrombin may assume an inactive conformation in the absence of Na(+) and that its procoagulant and anticoagulant activities are closely linked to the mobility of residue 215.
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Allostery is a common mechanism of regulation of enzyme activity and specificity, and its signatures are readily identified from functional studies. For many allosteric systems, structural evidence exists of long-range communication among protein domains, but rarely has this communication been traced to a detailed pathway. The thrombin mutant D102N is stabilized in a self-inhibited conformation where access to the active site is occluded by a collapse of the entire 215-219 beta-strand. Binding of a fragment of the protease activated receptor PAR1 to exosite I, 30-A away from the active site region, causes a large conformational change that corrects the position of the 215-219 beta-strand and restores access to the active site. The crystal structure of the thrombin-PAR1 complex, solved at 2.2-A resolution, reveals the details of this long-range allosteric communication in terms of a network of polar interactions.
==Disease==
==Disease==
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==Reference==
==Reference==
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Crystal structure of thrombin in a self-inhibited conformation., Pineda AO, Chen ZW, Bah A, Garvey LC, Mathews FS, Di Cera E, J Biol Chem. 2006 Oct 27;281(43):32922-8. Epub 2006 Sep 5. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16954215 16954215]
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Structural identification of the pathway of long-range communication in an allosteric enzyme., Gandhi PS, Chen Z, Mathews FS, Di Cera E, Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):1832-7. Epub 2008 Feb 4. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/18250335 18250335]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Protein complex]]
[[Category: Protein complex]]
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[[Category: Gandhi, P S.]]
[[Category: Gandhi, P S.]]
[[Category: Mathews, F S.]]
[[Category: Mathews, F S.]]
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[[Category: acute phase]]
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[[Category: Acute phase]]
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[[Category: blood coagulation]]
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[[Category: Blood coagulation]]
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[[Category: calcium]]
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[[Category: Calcium]]
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[[Category: cleavage on pair of basic residue]]
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[[Category: Cleavage on pair of basic residue]]
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[[Category: disease mutation]]
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[[Category: Disease mutation]]
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[[Category: gamma-carboxyglutamic acid]]
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[[Category: Gamma-carboxyglutamic acid]]
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[[Category: glycoprotein]]
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[[Category: Glycoprotein]]
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[[Category: hydrolase]]
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[[Category: Hydrolase]]
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[[Category: kringle]]
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[[Category: Kringle]]
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[[Category: polymorphism]]
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[[Category: Polymorphism]]
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[[Category: secreted]]
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[[Category: Secreted]]
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[[Category: serine protease]]
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[[Category: Serine protease]]
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[[Category: zymogen]]
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[[Category: Zymogen]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Apr 30 13:37:40 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 05:25:31 2008''
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Revision as of 10:37, 30 April 2008

Image:3bei.jpg

Template:STRUCTURE 3bei

Crystal structure of the slow form of thrombin in a self_inhibited conformation


Contents

Overview

Allostery is a common mechanism of regulation of enzyme activity and specificity, and its signatures are readily identified from functional studies. For many allosteric systems, structural evidence exists of long-range communication among protein domains, but rarely has this communication been traced to a detailed pathway. The thrombin mutant D102N is stabilized in a self-inhibited conformation where access to the active site is occluded by a collapse of the entire 215-219 beta-strand. Binding of a fragment of the protease activated receptor PAR1 to exosite I, 30-A away from the active site region, causes a large conformational change that corrects the position of the 215-219 beta-strand and restores access to the active site. The crystal structure of the thrombin-PAR1 complex, solved at 2.2-A resolution, reveals the details of this long-range allosteric communication in terms of a network of polar interactions.

Disease

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

About this Structure

3BEI is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Structural identification of the pathway of long-range communication in an allosteric enzyme., Gandhi PS, Chen Z, Mathews FS, Di Cera E, Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):1832-7. Epub 2008 Feb 4. PMID:18250335 Page seeded by OCA on Wed Apr 30 13:37:40 2008

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OCA

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