Using ancient protein kinases to unravel a modern cancer drug’s mechanism

Wilson, C.; Agafonov, R. V.; Hoemberger, M.; Kutter, S.; Zorba, A.; Halpin, J.; Buosi, V.; Otten, R.; Waterman, D.; Theobald, D. L.; Kern, D.

doi:10.1126/science.aaa1823

Title: Using ancient protein kinases to unravel a modern cancer drug’s mechanism

Journal Article · Fri Feb 20 00:00:00 EST 2015 · Science

DOI:https://doi.org/10.1126/science.aaa1823· OSTI ID:1353298

Wilson, C. ^[1]; Agafonov, R. V. ^[1]; Hoemberger, M. ^[1]; Kutter, S. ^[1]; Zorba, A. ^[1]; Halpin, J. ^[1]; Buosi, V. ^[1]; Otten, R. ^[1]; Waterman, D. ^[1]; Theobald, D. L. ^[2]; Kern, D. ^[1]

Howard Hughes Medical Institute and Department of Biochemistry, Brandeis University, Waltham, MA 02452, USA.
Department of Biochemistry, Brandeis University, Waltham, MA 02452, USA.

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.

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Research Organization:: Brandeis Univ., Waltham, MA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: FG02-05ER15699

OSTI ID:: 1353298

Alternate ID(s):: OSTI ID: 1345041

Journal Information:: Science, Journal Name: Science Vol. 347 Journal Issue: 6224; ISSN 0036-8075

Publisher:: American Association for the Advancement of Science (AAAS)Copyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 102 works

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