1sgi: Difference between revisions
New page: left|200px<br /> <applet load="1sgi" size="450" color="white" frame="true" align="right" spinBox="true" caption="1sgi, resolution 2.30Å" /> '''Crystal structure o... |
No edit summary |
||
| Line 1: | Line 1: | ||
[[Image:1sgi.gif|left|200px]]<br /> | [[Image:1sgi.gif|left|200px]]<br /><applet load="1sgi" size="350" color="white" frame="true" align="right" spinBox="true" | ||
<applet load="1sgi" size=" | |||
caption="1sgi, resolution 2.30Å" /> | caption="1sgi, resolution 2.30Å" /> | ||
'''Crystal structure of the anticoagulant slow form of thrombin'''<br /> | '''Crystal structure of the anticoagulant slow form of thrombin'''<br /> | ||
==Overview== | ==Overview== | ||
Na(+) binding near the primary specificity pocket of thrombin promotes the | 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== | ==Disease== | ||
| Line 11: | Line 10: | ||
==About this Structure== | ==About this Structure== | ||
1SGI is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with NAG as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [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] Full crystallographic information is available from [http:// | 1SGI is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=NAG:'>NAG</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1SGI OCA]. | ||
==Reference== | ==Reference== | ||
| Line 18: | Line 17: | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
[[Category: Thrombin]] | [[Category: Thrombin]] | ||
[[Category: Bush, L | [[Category: Bush, L A.]] | ||
[[Category: Caccia, S.]] | [[Category: Caccia, S.]] | ||
[[Category: Carrell, C | [[Category: Carrell, C J.]] | ||
[[Category: Cera, E | [[Category: Cera, E Di.]] | ||
[[Category: Chen, Z | [[Category: Chen, Z W.]] | ||
[[Category: Mathews, F | [[Category: Mathews, F S.]] | ||
[[Category: Pineda, A | [[Category: Pineda, A O.]] | ||
[[Category: Prasad, S.]] | [[Category: Prasad, S.]] | ||
[[Category: NAG]] | [[Category: NAG]] | ||
| Line 30: | Line 29: | ||
[[Category: thrombin]] | [[Category: thrombin]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:01:13 2008'' | ||
Revision as of 16:01, 21 February 2008
|
Crystal structure of the anticoagulant slow form of thrombin
OverviewOverview
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.
DiseaseDisease
Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]
About this StructureAbout this Structure
1SGI is a Protein complex structure of sequences from Homo sapiens with as ligand. Active as Thrombin, with EC number 3.4.21.5 Full crystallographic information is available from OCA.
ReferenceReference
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 Thu Feb 21 15:01:13 2008