Abstract
The serine proteinase plasmin is the key fibrinolytic enzyme that dissolves blood clots and also promotes cell migration and tissue remodeling. Here, we report the 2.65 Å crystal structure of a ternary complex of microplasmin–staphylokinase bound to a second microplasmin. The staphylokinase 'cofactor' does not affect the active-site geometry of the plasmin 'enzyme', but instead modifies its subsite specificity by providing additional docking sites for enhanced presentation of the plasminogen 'substrate' to the 'enzymes's' active site. The activation loop of the plasmin 'substrate', cleaved in these crystals, can be reconstructed to show how it runs across the active site of the plasmin 'enzyme' prior to activation cleavage. This is the first experimental structure of a productive proteinase–cofactor–macromolecular substrate complex. Furthermore, it provides a template for the design of improved plasminogen activators and plasmin inhibitors with considerable therapeutical potential.
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Acknowledgements
We thank G. P. Bourenkov and H. Bartunik for technical assistance at DESY, E. Kopetzki for help with protein expression and refolding, P. Fuentes for laboratory assistance, and R. Engh and M. Stubbs for reading the manuscript. This work was supported by the EEC programs 'Human Capital and Mobility' and 'Biotechnology', and by the Deutsche Forschungsgemeinschaft.
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Parry, M., Fernandez-Catalan, C., Bergner, A. et al. The ternary microplasmin–staphylokinase– microplasmin complex is a proteinase–cofactor– substrate complex in action. Nat Struct Mol Biol 5, 917–923 (1998). https://doi.org/10.1038/2359
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DOI: https://doi.org/10.1038/2359
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