3bei: Difference between revisions
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|PDB= 3bei |SIZE=350|CAPTION= <scene name='initialview01'>3bei</scene>, resolution 1.55Å | |PDB= 3bei |SIZE=350|CAPTION= <scene name='initialview01'>3bei</scene>, resolution 1.55Å | ||
|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> | |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> | ||
|LIGAND= <scene name='pdbligand= | |LIGAND= <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene> | ||
|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] | |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]) | ||
|DOMAIN= | |||
|RELATEDENTRY=[[3bef|3BEF]], [[2gp9|2GP9]] | |||
|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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==Overview== | ==Overview== | ||
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 --> fast transition. The structure shows an unprecedented self-inhibited conformation where Trp-215 and Arg-221a relocate >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. | 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 --> fast transition. The structure shows an unprecedented self-inhibited conformation where Trp-215 and Arg-221a relocate >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. | ||
==Disease== | |||
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: 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]] | ||
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[[Category: zymogen]] | [[Category: zymogen]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 05:25:31 2008'' | ||
Revision as of 05:25, 31 March 2008
| |||||||
| , resolution 1.55Å | |||||||
|---|---|---|---|---|---|---|---|
| Sites: | , and | ||||||
| Ligands: | , | ||||||
| Gene: | F2 (Homo sapiens) | ||||||
| Activity: | Thrombin, with EC number 3.4.21.5 | ||||||
| Related: | 3BEF, 2GP9
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal structure of the slow form of thrombin in a self_inhibited conformation
OverviewOverview
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 --> fast transition. The structure shows an unprecedented self-inhibited conformation where Trp-215 and Arg-221a relocate >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.
DiseaseDisease
Known disease associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]
About this StructureAbout this Structure
3BEI is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
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:16954215
Page seeded by OCA on Mon Mar 31 05:25:31 2008