Using ancient protein kinases to unravel a modern cancer drug's mechanism [electronic resource].
- Washington, D.C. : United States. Dept. of Energy, 2015.
Oak Ridge, Tenn. : Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy
- Physical Description:
- pages 882-886 : digital, PDF file
- Additional Creators:
- United States. Department of Energy. Office of Management
United States. Department of Energy
United States. Department of Energy. Office of Scientific and Technical Information
- Macromolecular function is rooted in energy landscapes, where sequence determines not a single structure but an ensemble of conformations. Hence, evolution modifies a protein’s function by altering its energy landscape. Consequently, we recreate the evolutionary pathway between two modern human oncogenes, Src and Abl, by reconstructing their common ancestors. Our evolutionary reconstruction combined with x-ray structures of the common ancestor and pre–steady-state kinetics reveals a detailed atomistic mechanism for selectivity of the successful cancer drug Gleevec. Gleevec affinity is gained during the evolutionary trajectory toward Abl and lost toward Src, primarily by shifting an induced-fit equilibrium that is also disrupted in the clinical T315I resistance mutation. Lastly, this work reveals the mechanism of Gleevec specificity while offering insights into how energy landscapes evolve.
- Published through SciTech Connect.
Science 347 6224 ISSN 0036-8075 AM
C. Wilson; R. V. Agafonov; M. Hoemberger; S. Kutter; A. Zorba; J. Halpin; V. Buosi; R. Otten; D. Waterman; D. L. Theobald; D. Kern.
- Funding Information:
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