Rational Design of Complex Formation between Plasminogen Activator Inhibitor-1 and Its Target Proteinases

• Published in: Journal of structural biology 1997-04, Vol.118 (3), p.236-242
• Main Authors: Aertgeerts, Kathleen, De Ranter, Camiel J., Booth, Nuala A., Declerck, Paul J.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Binding Sites - genetics; Endopeptidases - chemistry; Endopeptidases - genetics; Endopeptidases - metabolism; In Vitro Techniques; Macromolecular Substances; Models, Molecular; Molecular Sequence Data; Molecular Structure; Plasminogen Activator Inhibitor 1 - chemistry; Plasminogen Activator Inhibitor 1 - genetics; Plasminogen Activator Inhibitor 1 - metabolism; Protein Conformation; Sequence Homology, Amino Acid; Serpins - chemistry; Serpins - genetics; Serpins - metabolism; Tissue Plasminogen Activator - chemistry; Tissue Plasminogen Activator - genetics; Tissue Plasminogen Activator - metabolism; Urokinase-Type Plasminogen Activator - chemistry; Urokinase-Type Plasminogen Activator - genetics; Urokinase-Type Plasminogen Activator - metabolism
• ISSN: 1047-8477; 1095-8657
• DOI: 10.1006/jsbi.1997.3860

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 differences in inhibition rate constants observed for the different proteinases can be explained from these models.