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'''HUMAN ALPHA-THROMBIN INHIBITION BY CBZ-PRO-AZALYS-ONP''' | '''HUMAN ALPHA-THROMBIN INHIBITION BY CBZ-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-carbobenzoxy-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 10:11:52 2008'' | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | |||
Revision as of 10:11, 2 May 2008
HUMAN ALPHA-THROMBIN INHIBITION BY CBZ-PRO-AZALYS-ONP
OverviewOverview
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 StructureAbout this Structure
1AFE is a Protein complex structure of sequences from Hirudo medicinalis and Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
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 10:11:52 2008