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

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 p... Full description

Journal Title: Science (New York N.Y.), February 20, 2015, Vol.347(6224), pp.882-886
Main Author: Wilson, C
Other Authors: Agafonov, R V , Hoemberger, M , Kutter, S , Zorba, A , Halpin, J , Buosi, V , Otten, R , Waterman, D , Theobald, D L , Kern, D
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1095-9203 ; DOI: 10.1126/science.aaa1823
Link: http://search.proquest.com/docview/1657328489/?pq-origsite=primo
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recordid: proquest1657328489
title: Kinase dynamics. Using ancient protein kinases to unravel a modern cancer drug's mechanism.
format: Article
creator:
  • Wilson, C
  • Agafonov, R V
  • Hoemberger, M
  • Kutter, S
  • Zorba, A
  • Halpin, J
  • Buosi, V
  • Otten, R
  • Waterman, D
  • Theobald, D L
  • Kern, D
subjects:
  • Antineoplastic Agents–Chemistry
  • Benzamides–Pharmacology
  • Drug Resistance, Neoplasm–Chemistry
  • Entropy–Pharmacology
  • Evolution, Molecular–Genetics
  • Humans–Chemistry
  • Imatinib Mesylate–Genetics
  • Mutation–Chemistry
  • Oncogene Proteins V-Abl–Pharmacology
  • Phylogeny–Chemistry
  • Piperazines–Pharmacology
  • Protein Binding–Chemistry
  • Protein Kinase Inhibitors–Pharmacology
  • Protein Structure, Secondary–Chemistry
  • Pyrimidines–Classification
  • Src-Family Kinases–Genetics
  • Antineoplastic Agents
  • Benzamides
  • Oncogene Proteins V-Abl
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Imatinib Mesylate
  • Src-Family Kinases
ispartof: Science (New York, N.Y.), February 20, 2015, Vol.347(6224), pp.882-886
description: 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. Science, this issue p. 882 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...
language: eng
source:
identifier: E-ISSN: 1095-9203 ; DOI: 10.1126/science.aaa1823
fulltext: no_fulltext
issn:
  • 10959203
  • 1095-9203
url: Link


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titleKinase dynamics. Using ancient protein kinases to unravel a modern cancer drug's mechanism.
creatorWilson, C ; Agafonov, R V ; Hoemberger, M ; Kutter, S ; Zorba, A ; Halpin, J ; Buosi, V ; Otten, R ; Waterman, D ; Theobald, D L ; Kern, D
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ispartofScience (New York, N.Y.), February 20, 2015, Vol.347(6224), pp.882-886
identifierE-ISSN: 1095-9203 ; DOI: 10.1126/science.aaa1823
subjectAntineoplastic Agents–Chemistry ; Benzamides–Pharmacology ; Drug Resistance, Neoplasm–Chemistry ; Entropy–Pharmacology ; Evolution, Molecular–Genetics ; Humans–Chemistry ; Imatinib Mesylate–Genetics ; Mutation–Chemistry ; Oncogene Proteins V-Abl–Pharmacology ; Phylogeny–Chemistry ; Piperazines–Pharmacology ; Protein Binding–Chemistry ; Protein Kinase Inhibitors–Pharmacology ; Protein Structure, Secondary–Chemistry ; Pyrimidines–Classification ; Src-Family Kinases–Genetics ; Antineoplastic Agents ; Benzamides ; Oncogene Proteins V-Abl ; Piperazines ; Protein Kinase Inhibitors ; Pyrimidines ; Imatinib Mesylate ; Src-Family Kinases
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descriptionThe 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. Science, this issue p. 882 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...
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