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Title: 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. 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.

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1]
  1. Brandeis Univ., Waltham, MA (United States)
Publication Date:
Research Org.:
Brandeis Univ., Waltham, MA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1345041
Grant/Contract Number:  
FG02-05ER15699
Resource Type:
Accepted Manuscript
Journal Name:
Science
Additional Journal Information:
Journal Volume: 347; Journal Issue: 6224; Journal ID: ISSN 0036-8075
Publisher:
AAAS
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

Wilson, C., Agafonov, R. V., Hoemberger, M., Kutter, S., Zorba, A., Halpin, J., Buosi, V., Otten, R., Waterman, D., Theobald, D. L., and Kern, D. Using ancient protein kinases to unravel a modern cancer drug's mechanism. United States: N. p., 2015. Web. doi:10.1126/science.aaa1823.
Wilson, C., Agafonov, R. V., Hoemberger, M., Kutter, S., Zorba, A., Halpin, J., Buosi, V., Otten, R., Waterman, D., Theobald, D. L., & Kern, D. Using ancient protein kinases to unravel a modern cancer drug's mechanism. United States. doi:10.1126/science.aaa1823.
Wilson, C., Agafonov, R. V., Hoemberger, M., Kutter, S., Zorba, A., Halpin, J., Buosi, V., Otten, R., Waterman, D., Theobald, D. L., and Kern, D. Thu . "Using ancient protein kinases to unravel a modern cancer drug's mechanism". United States. doi:10.1126/science.aaa1823. https://www.osti.gov/servlets/purl/1345041.
@article{osti_1345041,
title = {Using ancient protein kinases to unravel a modern cancer drug's mechanism},
author = {Wilson, C. and Agafonov, R. V. and Hoemberger, M. and Kutter, S. and Zorba, A. and Halpin, J. and Buosi, V. and Otten, R. and Waterman, D. and Theobald, D. L. and Kern, D.},
abstractNote = {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.},
doi = {10.1126/science.aaa1823},
journal = {Science},
number = 6224,
volume = 347,
place = {United States},
year = {2015},
month = {2}
}

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Cited by: 43 works
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