3bv9

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
Line 7: Line 7:
|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>
|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=
+
|DOMAIN=<span class='plainlinks'>[http://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?uid=cd00190 Tryp_SPc]</span>
|RELATEDENTRY=[[1sfq|1SFQ]]
|RELATEDENTRY=[[1sfq|1SFQ]]
|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>
|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>
Line 16: Line 16:
==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.
+
Background: Novel pentapeptides called Thrombostatin FM compounds consisting mostly of D-isomers and unusual amino acids were prepared based upon the stable angiotensin converting enzyme breakdown product of bradykinin - RPPGF. Methods and Results: These peptides are direct thrombin inhibitors prolonging the thrombin clotting time, APTT, and PT at &gt;/= 0.78, 1.6 and 1.6 muM, respectively. They competitively inhibit alpha-thrombin-induced cleavage of a chromogenic substrate at 4.4-8.2 muM. They do not significantly inhibit plasma kallikrein, FXIIa, FXIa, FIXa, FVIIa-TF, FXa, plasmin or cathepsin G. One form, FM19 [rOicPaF(p-Me)], blocks alpha-thrombin induced calcium flux in fibroblasts with an IC(50) of 6.9 +/- 1.2 muM. FM19 achieved 100% inhibition of threshold alpha- or gamma-thrombin-induced platelet aggregation at 8.4 +/- 4.7 muM and 16 +/- 4 muM, respectively. The crystal structure of thrombin in complex with FM19 shows that the N-terminal D-Arg retrobinds into the S1 pocket, its 2nd residue Oic interacts with His-57, Tyr-60a and Trp-60d, and its C-terminal p-methyl Phe engages thrombin's aryl binding site composed of Ile-174, Trp-215 and Leu-99. When administered intraperitoneal, intraduodenal, or orally to mice, FM19 prolongs thrombin clotting times and delays carotid artery thrombosis. Conclusion: FM19, a low affinity reversible direct thrombin inhibitor, might be useful as an add-on agent to address an unmet need in platelet inhibition in acute coronary syndromes in diabetics and others who with all current anti-platelet therapy still have reactive platelets.
==Disease==
==Disease==
Line 25: Line 25:
==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]
+
Thrombostatin FM compounds: direct thrombin inhibitors - mechanism of action in vitro and in vivo., Nieman MT, Burke F, Warnock M, Zhou Y, Sweigart J, Chen A, Ricketts D, Lucchesi BR, Chen Z, Di Cera E, Hilfinger J, Kim JS, Mosberg HI, Schmaier AH, J Thromb Haemost. 2008 Feb 25;. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/18315550 18315550]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Protein complex]]
[[Category: Protein complex]]
Line 56: Line 56:
[[Category: zymogen]]
[[Category: zymogen]]
-
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 05:29:16 2008''
+
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Apr 2 11:32:50 2008''

Revision as of 08:32, 2 April 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
Domains: Tryp_SPc
Related: 1SFQ


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



Structure of Thrombin Bound to the Inhibitor FM19


Contents

Overview

Background: Novel pentapeptides called Thrombostatin FM compounds consisting mostly of D-isomers and unusual amino acids were prepared based upon the stable angiotensin converting enzyme breakdown product of bradykinin - RPPGF. Methods and Results: These peptides are direct thrombin inhibitors prolonging the thrombin clotting time, APTT, and PT at >/= 0.78, 1.6 and 1.6 muM, respectively. They competitively inhibit alpha-thrombin-induced cleavage of a chromogenic substrate at 4.4-8.2 muM. They do not significantly inhibit plasma kallikrein, FXIIa, FXIa, FIXa, FVIIa-TF, FXa, plasmin or cathepsin G. One form, FM19 [rOicPaF(p-Me)], blocks alpha-thrombin induced calcium flux in fibroblasts with an IC(50) of 6.9 +/- 1.2 muM. FM19 achieved 100% inhibition of threshold alpha- or gamma-thrombin-induced platelet aggregation at 8.4 +/- 4.7 muM and 16 +/- 4 muM, respectively. The crystal structure of thrombin in complex with FM19 shows that the N-terminal D-Arg retrobinds into the S1 pocket, its 2nd residue Oic interacts with His-57, Tyr-60a and Trp-60d, and its C-terminal p-methyl Phe engages thrombin's aryl binding site composed of Ile-174, Trp-215 and Leu-99. When administered intraperitoneal, intraduodenal, or orally to mice, FM19 prolongs thrombin clotting times and delays carotid artery thrombosis. Conclusion: FM19, a low affinity reversible direct thrombin inhibitor, might be useful as an add-on agent to address an unmet need in platelet inhibition in acute coronary syndromes in diabetics and others who with all current anti-platelet therapy still have reactive platelets.

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

Thrombostatin FM compounds: direct thrombin inhibitors - mechanism of action in vitro and in vivo., Nieman MT, Burke F, Warnock M, Zhou Y, Sweigart J, Chen A, Ricketts D, Lucchesi BR, Chen Z, Di Cera E, Hilfinger J, Kim JS, Mosberg HI, Schmaier AH, J Thromb Haemost. 2008 Feb 25;. PMID:18315550

Page seeded by OCA on Wed Apr 2 11:32:50 2008

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3bv9"
Personal tools