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

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.

SUBMITTER: Wilson C

PROVIDER: S-EPMC4405104 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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

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

Science (New York, N.Y.) 20150201 6224

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 m ...[more]

PMID: 25700521

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