1ygc: Difference between revisions
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'''Short Factor VIIa with a small molecule inhibitor'''<br /> | '''Short Factor VIIa with a small molecule inhibitor'''<br /> | ||
==Overview== | ==Overview== | ||
The serine protease factor VIIa (FVIIa) in complex with its cellular | The serine protease factor VIIa (FVIIa) in complex with its cellular cofactor tissue factor (TF) initiates the blood coagulation reactions. TF.FVIIa is also implicated in thrombosis-related disorders and constitutes an appealing therapeutic target for treatment of cardiovascular diseases. To this end, we generated the FVIIa active site inhibitor G17905, which displayed great potency toward TF.FVIIa (Ki = 0.35 +/- 0.11 nM). G17905 did not appreciably inhibit 12 of the 14 examined trypsin-like serine proteases, consistent with its TF.FVIIa-specific activity in clotting assays. The crystal structure of the FVIIa.G17905 complex provides insight into the molecular basis of the high selectivity. It shows that, compared with other serine proteases, FVIIa is uniquely equipped to accommodate conformational disturbances in the Gln217-Gly219 region caused by the ortho-hydroxy group of the inhibitor's aminobenzamidine moiety located in the S1 recognition pocket. Moreover, the structure revealed a novel, nonstandard conformation of FVIIa active site in the region of the oxyanion hole, a "flipped" Lys192-Gly193 peptide bond. Macromolecular substrate activation assays demonstrated that G17905 is a noncompetitive, slow-binding inhibitor. Nevertheless, G17905 effectively inhibited thrombus formation in a baboon arterio-venous shunt model, reducing platelet and fibrin deposition by approximately 70% at 0.4 mg/kg + 0.1 mg/kg/min infusion. Therefore, the in vitro potency of G17905, characterized by slow binding kinetics, correlated with efficacious antithrombotic activity in vivo. | ||
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
1YGC 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 CA, SO4 and 905 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Coagulation_factor_VIIa Coagulation factor VIIa], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.21 3.4.21.21] Full crystallographic information is available from [http:// | 1YGC 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=CA:'>CA</scene>, <scene name='pdbligand=SO4:'>SO4</scene> and <scene name='pdbligand=905:'>905</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Coagulation_factor_VIIa Coagulation factor VIIa], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.21 3.4.21.21] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1YGC OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
[[Category: Artis, D | [[Category: Artis, D R.]] | ||
[[Category: Bunting, S.]] | [[Category: Bunting, S.]] | ||
[[Category: Eigenbrot, C.]] | [[Category: Eigenbrot, C.]] | ||
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[[Category: Goldsmith, R.]] | [[Category: Goldsmith, R.]] | ||
[[Category: Kirchhofer, D.]] | [[Category: Kirchhofer, D.]] | ||
[[Category: Olivero, A | [[Category: Olivero, A G.]] | ||
[[Category: Rawson, T.]] | [[Category: Rawson, T.]] | ||
[[Category: Refino, C.]] | [[Category: Refino, C.]] | ||
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[[Category: inverted oxy-anion hole]] | [[Category: inverted oxy-anion hole]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:05:03 2008'' | ||
Revision as of 17:05, 21 February 2008
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Short Factor VIIa with a small molecule inhibitor
OverviewOverview
The serine protease factor VIIa (FVIIa) in complex with its cellular cofactor tissue factor (TF) initiates the blood coagulation reactions. TF.FVIIa is also implicated in thrombosis-related disorders and constitutes an appealing therapeutic target for treatment of cardiovascular diseases. To this end, we generated the FVIIa active site inhibitor G17905, which displayed great potency toward TF.FVIIa (Ki = 0.35 +/- 0.11 nM). G17905 did not appreciably inhibit 12 of the 14 examined trypsin-like serine proteases, consistent with its TF.FVIIa-specific activity in clotting assays. The crystal structure of the FVIIa.G17905 complex provides insight into the molecular basis of the high selectivity. It shows that, compared with other serine proteases, FVIIa is uniquely equipped to accommodate conformational disturbances in the Gln217-Gly219 region caused by the ortho-hydroxy group of the inhibitor's aminobenzamidine moiety located in the S1 recognition pocket. Moreover, the structure revealed a novel, nonstandard conformation of FVIIa active site in the region of the oxyanion hole, a "flipped" Lys192-Gly193 peptide bond. Macromolecular substrate activation assays demonstrated that G17905 is a noncompetitive, slow-binding inhibitor. Nevertheless, G17905 effectively inhibited thrombus formation in a baboon arterio-venous shunt model, reducing platelet and fibrin deposition by approximately 70% at 0.4 mg/kg + 0.1 mg/kg/min infusion. Therefore, the in vitro potency of G17905, characterized by slow binding kinetics, correlated with efficacious antithrombotic activity in vivo.
DiseaseDisease
Known diseases associated with this structure: Factor VII deficiency OMIM:[227500], Myocardial infarction, decreased susceptibility to OMIM:[227500]
About this StructureAbout this Structure
1YGC is a Protein complex structure of sequences from Homo sapiens with , and as ligands. Active as Coagulation factor VIIa, with EC number 3.4.21.21 Full crystallographic information is available from OCA.
ReferenceReference
A selective, slow binding inhibitor of factor VIIa binds to a nonstandard active site conformation and attenuates thrombus formation in vivo., Olivero AG, Eigenbrot C, Goldsmith R, Robarge K, Artis DR, Flygare J, Rawson T, Sutherlin DP, Kadkhodayan S, Beresini M, Elliott LO, DeGuzman GG, Banner DW, Ultsch M, Marzec U, Hanson SR, Refino C, Bunting S, Kirchhofer D, J Biol Chem. 2005 Mar 11;280(10):9160-9. Epub 2005 Jan 4. PMID:15632123
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