3bef: Difference between revisions

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[[Image:3bef.jpg|left|200px]]
[[Image:3bef.jpg|left|200px]]


{{Structure
<!--
|PDB= 3bef |SIZE=350|CAPTION= <scene name='initialview01'>3bef</scene>, resolution 2.20&Aring;
The line below this paragraph, containing "STRUCTURE_3bef", creates the "Structure Box" on the page.
|SITE= <scene name='pdbsite=AC1:Nag+Binding+Site+For+Residue+E+302'>AC1</scene>
You may change the PDB parameter (which sets the PDB file loaded into the applet)  
|LIGAND= <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>
or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
|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>
or leave the SCENE parameter empty for the default display.
|GENE= F2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]), F2R, CF2R, PAR1, TR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
-->
|DOMAIN=
{{STRUCTURE_3bef|  PDB=3bef |  SCENE= }}  
|RELATEDENTRY=[[1shh|1SHH]], [[2gp9|2GP9]], [[3bei|3BEI]]
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3bef FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3bef OCA], [http://www.ebi.ac.uk/pdbsum/3bef PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=3bef RCSB]</span>
}}


'''Crystal structure of thrombin bound to the extracellular fragment of PAR1'''
'''Crystal structure of thrombin bound to the extracellular fragment of PAR1'''
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==Overview==
==Overview==
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 --&gt; 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.
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==
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:[http://www.ncbi.nlm.nih.gov/pubmed/15152000 15152000]
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.]]
[[Category: acute phase]]
[[Category: Acute phase]]
[[Category: blood coagulation]]
[[Category: Blood coagulation]]
[[Category: calcium]]
[[Category: Calcium]]
[[Category: cleavage on pair of basic residue]]
[[Category: Cleavage on pair of basic residue]]
[[Category: disease mutation]]
[[Category: Disease mutation]]
[[Category: g-protein coupled receptor]]
[[Category: G-protein coupled receptor]]
[[Category: gamma-carboxyglutamic acid]]
[[Category: Gamma-carboxyglutamic acid]]
[[Category: glycoprotein]]
[[Category: Glycoprotein]]
[[Category: hydrolase]]
[[Category: Hydrolase]]
[[Category: kringle]]
[[Category: Kringle]]
[[Category: membrane]]
[[Category: Membrane]]
[[Category: phosphoprotein]]
[[Category: Phosphoprotein]]
[[Category: polymorphism]]
[[Category: Polymorphism]]
[[Category: receptor]]
[[Category: Receptor]]
[[Category: secreted]]
[[Category: Secreted]]
[[Category: serine protease]]
[[Category: Serine protease]]
[[Category: transducer]]
[[Category: Transducer]]
[[Category: transmembrane]]
[[Category: Transmembrane]]
[[Category: zymogen]]
[[Category: Zymogen]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Apr 30 13:37:37 2008''
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 05:25:30 2008''

Revision as of 10:37, 30 April 2008

File:3bef.jpg

Template:STRUCTURE 3bef

Crystal structure of thrombin bound to the extracellular fragment of PAR1


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

3BEF 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 13:37:37 2008

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