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Science. 2015 Feb 20;347(6224):882-6. doi: 10.1126/science.aaa1823.

Kinase dynamics. Using ancient protein kinases to unravel a modern cancer drug's mechanism.

Author information

1
Howard Hughes Medical Institute and Department of Biochemistry, Brandeis University, Waltham, MA 02452, USA.
2
Department of Biochemistry, Brandeis University, Waltham, MA 02452, USA.
3
Howard Hughes Medical Institute and Department of Biochemistry, Brandeis University, Waltham, MA 02452, USA. dkern@brandeis.edu.

Abstract

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. Here, 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. This work reveals the mechanism of Gleevec specificity while offering insights into how energy landscapes evolve.

PMID:
25700521
PMCID:
PMC4405104
DOI:
10.1126/science.aaa1823
[Indexed for MEDLINE]
Free PMC Article

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