1ae8

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spinqualitylabelsall models 1ae8, resolution 2.0Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

HUMAN ALPHA-THROMBIN INHIBITION BY EOC-D-PHE-PRO-AZALYS-ONP

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

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.

Disease

Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]

About this Structure

1AE8 is a Protein complex structure of sequences from Hirudo medicinalis and Homo sapiens with NAG and AZL as ligands. Active as Thrombin, with EC number 3.4.21.5 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

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