Tissue plasminogen activator (tPA) plays a crucial role in the breakdown of blood clots in patients suffering from thromboembolic diseases. A recombinant tPA better suited for this purpose, reteplase, has been developed by deleting the kringle-1, finger, and epidermal growth factor domains of the protein to improve its half life and lower its affinity to fibrin. However, this mutant’s three dimensional structure has yet to be elucidated, and a core understanding of its structure is vital for further improvement of its activity. Previous protein-protein docking of the two domains of this enzyme, the kringle-2 and protease domain, have given a general orientation and position of the enzyme’s shape. In this work, structure prediction of reteplase is conducted using Rosetta ab initio and Rosetta comparative modeling protocols, using the docking results as a template. Preliminary data shows no convergence of de novo generated structures. However, the results of these calculations are expected to provide insight of the structure-function relationship of reteplase, as well as be useful for further improvement upon this enzyme’s capability as a medicinal tool.

Ab initio structure prediction and homology modeling of recombinant tissue plasminogen activator

2019 Spring National Meeting

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