Abstract
The EGF receptor (EGFR) regulates important cellular processes including proliferation, differentiation, and apoptosis. EGFR is frequently overexpressed in a range of cancers and is associated with disease progression and treatment. Clinical studies have shown that EGFR mutations confer tumor sensitivity to tyrosine kinase inhibitors in patients with non-small cell lung cancer. In this study, we have conducted molecular dynamics simulations over several microseconds for wild-type and L858R mutant forms of EGFR in the ligand-free state. Close inspection of the conformations and interactions within the binding pocket reveals, converse to the wild type, that the mutant EGFR prefers to bind gefitinib, a targeted anticancer drug, rather than ATP, offering an explanation for why gefitinib is more effective in patients with EGFR mutations than those without.
©2012 AACR.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / metabolism
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Binding Sites
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Enzyme Stability / drug effects
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ErbB Receptors / antagonists & inhibitors*
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ErbB Receptors / chemistry
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Gefitinib
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Humans
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Hydrophobic and Hydrophilic Interactions
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Ligands
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Molecular Dynamics Simulation*
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Mutant Proteins / antagonists & inhibitors
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Mutant Proteins / chemistry
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Mutation / genetics
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Principal Component Analysis
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Protein Binding / drug effects
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Protein Structure, Secondary
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Protein Structure, Tertiary
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Quinazolines / chemistry
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Quinazolines / pharmacology
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Time Factors
Substances
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Antineoplastic Agents
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Ligands
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Mutant Proteins
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Protein Kinase Inhibitors
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Quinazolines
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Adenosine Triphosphate
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ErbB Receptors
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Gefitinib