3bv9

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|PDB= 3bv9 |SIZE=350|CAPTION= <scene name='initialview01'>3bv9</scene>, resolution 1.80&Aring;
|PDB= 3bv9 |SIZE=350|CAPTION= <scene name='initialview01'>3bv9</scene>, resolution 1.80&Aring;
|SITE= <scene name='pdbsite=AC1:Oic+Binding+Site+For+Residue+C+402'>AC1</scene>, <scene name='pdbsite=AC2:4ph+Binding+Site+For+Residue+C+405'>AC2</scene>, <scene name='pdbsite=AC3:Iod+Binding+Site+For+Residue+B+303'>AC3</scene>, <scene name='pdbsite=AC4:Na+Binding+Site+For+Residue+B+307'>AC4</scene>, <scene name='pdbsite=AC5:Nh2+Binding+Site+For+Residue+C+406'>AC5</scene> and <scene name='pdbsite=AC6:Gol+Binding+Site+For+Residue+B+305'>AC6</scene>
|SITE= <scene name='pdbsite=AC1:Oic+Binding+Site+For+Residue+C+402'>AC1</scene>, <scene name='pdbsite=AC2:4ph+Binding+Site+For+Residue+C+405'>AC2</scene>, <scene name='pdbsite=AC3:Iod+Binding+Site+For+Residue+B+303'>AC3</scene>, <scene name='pdbsite=AC4:Na+Binding+Site+For+Residue+B+307'>AC4</scene>, <scene name='pdbsite=AC5:Nh2+Binding+Site+For+Residue+C+406'>AC5</scene> and <scene name='pdbsite=AC6:Gol+Binding+Site+For+Residue+B+305'>AC6</scene>
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|LIGAND= <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene> and <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>
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|LIGAND= <scene name='pdbligand=4PH:4-METHYL-L-PHENYLALANINE'>4PH</scene>, <scene name='pdbligand=DAL:D-ALANINE'>DAL</scene>, <scene name='pdbligand=DAR:D-ARGININE'>DAR</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=OIC:OCTAHYDROINDOLE-2-CARBOXYLIC+ACID'>OIC</scene>
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|ACTIVITY= [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]
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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>
|GENE= F2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
|GENE= F2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
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|DOMAIN=
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|RELATEDENTRY=[[1sfq|1SFQ]]
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3bv9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3bv9 OCA], [http://www.ebi.ac.uk/pdbsum/3bv9 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=3bv9 RCSB]</span>
}}
}}
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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.
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.
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==Disease==
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Known disease associated with this structure: Dysprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]], Hyperprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]], Hypoprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]]
==About this Structure==
==About this Structure==
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[[Category: Warnock, M.]]
[[Category: Warnock, M.]]
[[Category: Zhou, Y.]]
[[Category: Zhou, Y.]]
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[[Category: GOL]]
 
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[[Category: IOD]]
 
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[[Category: NA]]
 
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[[Category: NH2]]
 
[[Category: acute phase]]
[[Category: acute phase]]
[[Category: blood coagulation]]
[[Category: blood coagulation]]
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[[Category: zymogen]]
[[Category: zymogen]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 19:01:28 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 05:29:16 2008''

Revision as of 02:29, 31 March 2008

Image:3bv9.jpg


PDB ID 3bv9

Drag the structure with the mouse to rotate
, resolution 1.80Å
Sites: , , , , and
Ligands: , , , , , , ,
Gene: F2 (Homo sapiens)
Activity: Thrombin, with EC number 3.4.21.5
Related: 1SFQ


Resources: FirstGlance, OCA, PDBsum, RCSB
Coordinates: save as pdb, mmCIF, xml



Structure of Thrombin Bound to the Inhibitor FM19


Contents

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 --> 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.

Disease

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

About this Structure

3BV9 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

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