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PDBsum entry 4csv
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References listed in PDB file
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Key reference
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Title
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Kinase dynamics. Using ancient protein kinases to unravel a modern cancer drug'S mechanism.
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Authors
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C.Wilson,
R.V.Agafonov,
M.Hoemberger,
S.Kutter,
A.Zorba,
J.Halpin,
V.Buosi,
R.Otten,
D.Waterman,
D.L.Theobald,
D.Kern.
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Ref.
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Science, 2015,
347,
882-886.
[DOI no: ]
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PubMed id
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Abstract
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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.
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