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Research Abstracts Online
January 2009 - March 2010

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University of Minnesota Twin Cities
Institute of Technology
Department of Chemistry

PI: Tai-Sung Lee

Simulation Studies of Clinically Observed JAK2 Mutations

The tyrosine kinase JAK2 is extremely important in triggering nuclear translocation and regulation of target genes expression through STAT pathways. The V617F mutation, resulting in deregulation of JAK2, has been implicated in the oncogenesis of chronic myeloproliferative diseases (MPDs). However, both the mechanism of JAK2 auto-inhibition and the mechanisms of constitutive activation due to V617F and other mutations are still unclear.

This researcher has recently utilized molecular dynamics (MD) simulation techniques to establish plausible mechanisms of JAK2 auto-inhibition and V617F constitutive activation at the atomic level, which the first to report simulation-derived mechanism of JAK2 auto-regulation. Quest Diagnostics, the researcher’s collaborator, has recently provided additional clinical mutation results of JAK2. Long-time MD simulations on those mutations will be performed based on the simulation-derived structure of JAK2, to rationalize the clinically observed phenotypes. The NAMD simulation package will be used in this project and the molecular system size is around 130,000 atoms. This work would advance the understanding of JAK2 mechanisms at the atomic level and possibly establish a framework for rational structure-based drug design for JAK2-related diseases.