Editors' ChoiceEVOLUTION

Evolution of dynamics affects function

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Sci. Signal.  24 Feb 2015:
Vol. 8, Issue 365, pp. ec47
DOI: 10.1126/scisignal.aaa9568

The drug Gleevac inhibits Abl kinases and is used to treat multiple cancers. The closely related Src kinases also play a role in cancer but are not inhibited effectively by Gleevac. Nevertheless, Gleevac-bound structures of Src and Abl are nearly identical. Based on this structural information and protein sequence data, Wilson et al. reconstructed the common ancestor of Src and Abl. Mutations that affected conformational dynamics caused Gleevac affinity to be gained on the evolutionary trajectory toward Abl and lost on the trajectory toward Src.

C. Wilson, R. V. Agafonov, M. Hoemberger, S. Kutter, A. Zorba, J. Halpin, V. Buosi, R. Otten, D. Waterman, D. L. Theobald, D. Kern, Using ancient protein kinases to unravel a modern cancer drug’s mechanism. Science 347, 882–886 (2015). [Abstract] [Full Text]