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'''HUMAN ALPHA-THROMBIN INHIBITION BY EOC-D-PHE-PRO-AZALYS-ONP''' | '''HUMAN ALPHA-THROMBIN INHIBITION BY EOC-D-PHE-PRO-AZALYS-ONP''' | ||
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[[Category: Simone, G De.]] | [[Category: Simone, G De.]] | ||
[[Category: Tarricone, C.]] | [[Category: Tarricone, C.]] | ||
[[Category: | [[Category: Blood coagulation]] | ||
[[Category: | [[Category: Glycosylated protein]] | ||
[[Category: N-ethoxycarbonyl-d-phe-pro-alfa-azalys-p-nitrophenylester]] | |||
[[Category: | [[Category: Serine proteinase inhibition]] | ||
[[Category: | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 10:09:14 2008'' | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | |||
Revision as of 07:09, 2 May 2008
HUMAN ALPHA-THROMBIN INHIBITION BY EOC-D-PHE-PRO-AZALYS-ONP
Overview
Kinetics, thermodynamics and structural aspects of human alpha-thrombin (thrombin) inhibition by newly synthesized low molecular weight derivatives of alpha-azalysine have been investigated. The thrombin catalyzed hydrolysis of N-ethoxycarbonyl-D-Phe-Pro-alpha-azaLys p-nitrophenyl ester (Eoc-D-Phe-Pro-azaLys-ONp) and N-carbobenzoxy-Pro-alpha-azaLys p-nitrophenyl ester (Cbz-Pro-azaLys-ONp) was investigated at pH 6.2 and 21.0 degrees C, and analyzed in parallel with that of N-alpha-(N,N-dimethylcarbamoyl)-alpha-azalysine p-nitrophenyl ester (Dmc-azaLys-ONp). Decarboxylation following the enzymatic hydrolysis of these p-nitrophenyl esters gave the corresponding 1-peptidyl-2(4-aminobutyl) hydrazines (peptidyl-Abh) showing properties of thrombin competitive inhibitors. Therefore, thermodynamics for the reversible binding of D-Phe-Pro-Abh, Cbz-Pro-Abh and Dmc-Abh to thrombin was examined. These results are consistent with the minimum four-step catalytic mechanism for product inhibition of serine proteinases. Eoc-D-Phe-Pro-azaLys-ONp and Eoc-D-Phe-Pro-Abh display a sub-micromolar affinity for thrombin together with a high selectivity versus homologous plasmatic and pancreatic serine proteinases acting on cationic substrates. The three-dimensional structures of the reversible non-covalent thrombin:Eoc-D-Phe-Pro-Abh and thrombin:Cbz-Pro-Abh complexes have been determined by X-ray crystallography at 2.0 A resolution (R-factor = 0.169 and 0.179, respectively), and analyzed in parallel with that of the thrombin:Dmc-azaLys acyl-enzyme adduct. Both Eoc-D-Phe-Pro-Abh and Cbz-Pro-Abh competitive inhibitors are accommodated in the thrombin active center, spanning the region between the aryl binding site and the S1 primary specificity subsite.
About this Structure
1AE8 is a Protein complex structure of sequences from Hirudo medicinalis and Homo sapiens. Full crystallographic information is available from OCA.
Reference
Human alpha-thrombin inhibition by the highly selective compounds N-ethoxycarbonyl-D-Phe-Pro-alpha-azaLys p-nitrophenyl ester and N-carbobenzoxy-Pro-alpha-azaLys p-nitrophenyl ester: a kinetic, thermodynamic and X-ray crystallographic study., De Simone G, Balliano G, Milla P, Gallina C, Giordano C, Tarricone C, Rizzi M, Bolognesi M, Ascenzi P, J Mol Biol. 1997 Jun 20;269(4):558-69. PMID:9217260 Page seeded by OCA on Fri May 2 10:09:14 2008
Proteopedia Page Contributors and Editors (what is this?)
- Pages with broken file links
- Hirudo medicinalis
- Homo sapiens
- Protein complex
- Thrombin
- Ascenzi, P.
- Balliano, G.
- Bolognesi, M.
- Gallina, C.
- Giordano, C.
- Milla, P.
- Rizzi, M.
- Simone, G De.
- Tarricone, C.
- Blood coagulation
- Glycosylated protein
- N-ethoxycarbonyl-d-phe-pro-alfa-azalys-p-nitrophenylester
- Serine proteinase inhibition
