Rational design of complex formation between plasminogen activator inhibitor-1 and its target proteinases

Journal of Structural Biology
K AertgeertsP J Declerck

Abstract

Considerable progress in understanding the mechanism of inhibition of proteinases by serpins has been obtained from different biochemical studies. These studies reveal that stable serpin/proteinase complex formation involves insertion of the reactive-site loop of the serpin and occurs at the acyl-enzyme stage. Even though no three-dimensional structure of a serpin/proteinase complex is resolved, structural information is available on some of the individual compounds. Molecular modeling techniques combined with recently acquired biochemical/biophysical data were used to provide insight into the stable complex formation between plasminogen activator inhibitor-1 (PAI-1) and the target proteinases: tissue-type plasminogen activator, urokinase-type plasminogen activator, and thrombin. This study reveals that PAI-1 initially interacts with its target proteinase when its reactive-site loop is solvent exposed and thereby accessible for the proteinase. Stable complex formation, however, involves the insertion of the reactive-site loop up to P7 and results in a tight binding geometry between PAI-1 and its target proteinase. The influence of different biologically relevant molecules on PAI-1/proteinase complex formation and the difference...Continue Reading

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Citations

Dec 22, 1999·Biochimica Et Biophysica Acta·N VleugelsP J Declerck
Mar 10, 2000·Biochimica Et Biophysica Acta·W Bode, R Huber
Apr 15, 2008·Journal of Structural Biology·Andrei N Lupas

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