Streptokinase (SK) is a plasminogen (Pg) activator secreted by a number of streptococcal strains. Kinetic analysis and equilibrium binding studies using active site fluorescently-labeled Pg and plasmin (Pm) has recently allowed dissection of the complicated mechanism of SK-induced Pg activation. Pg binding is aided by interactions between the COOH-terminal lysine residue of SK and one of the five kringle domains of the Pg zymogen. Compelling evidence indicates that the NH2-terminal residues of the bacterial activator insert into the Pg activation pocket. Interactions mediated by these residues, which mimic the endogenous NH2-terminus of the Pm catalytic domain, and stabilization of loops surrounding the active site, force SK-bound Pg to adopt a catalytically competent conformation (Pg*). Thus, SK functions according to the “molecular sexuality mechanism” of cofactor-induced zymogen activation. The SK·Pg* complex binds a second Pg molecule as substrate, and proteolytically converts it into Pm. Because SK has a much higher affinity for the product, Pm, than for substrate Pg, SK·Pm complex rapidly becomes the dominant species, which terminates the initial triggering catalytic cycle of Pg activation; SK·Pm then converts the remaining Pg molecules into Pm in a second catalytic cycle (the bullet cycle). Current investigations focus on areas of Pg*/Pm-bound SK that interact with the Pg substrate; recent results demonstrate that two consecutive Lys residues of the central SK domain play a key role in this regard. Further work on the mechanism of Pm generation would allow developing drugs that selectively target the SK·Pg*/SK·Pm complexes to treat severe streptococcal infections world-wide.
KeywordsCatalytic Domain Necrotizing Fasciitis Streptococcal Infection Fibrinolytic Agent Catalytic Complex
Research from the authors’ laboratories was supported by National Institutes of Health Grant HL056181 from the Heart, Lung, and Blood Institute to P. E. B. and SAF2007-64140 from Spanish Ministerio de Ciencia e Innovación (MICINN) to P. F.-P.
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