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PDBsum entry 4i21
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Transferase/transferase inhibitor
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PDB id
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4i21
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References listed in PDB file
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Key reference
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Title
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Insights into the aberrant activity of mutant egfr kinase domain and drug recognition.
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Authors
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K.S.Gajiwala,
J.Feng,
R.Ferre,
K.Ryan,
O.Brodsky,
S.Weinrich,
J.C.Kath,
A.Stewart.
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Ref.
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Structure, 2013,
21,
209-219.
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PubMed id
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Abstract
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The oncogenicity of the L858R mutant form of the epidermal growth factor
receptor (EGFR) in non-small-cell lung cancer is thought to be due to the
constitutive activation of its kinase domain. The selectivity of the marketed
drugs gefitinib and erlotinib for L858R mutant is attributed to their specific
recognition of the active kinase and to weaker ATP binding by L858R EGFR. We
present crystal structures showing that neither L858R nor the drug-resistant
L858R+T790M EGFR kinase domain is in the constitutively active conformation.
Additional co-crystal structures show that gefitinib and dacomitinib, an
irreversible anilinoquinazoline derivative currently in clinical development,
may not be conformation specific for the active state of the enzyme. Structural
data further reveal the potential mode of recognition of one of the
autophosphorylation sites in the C-terminal tail, Tyr-1016, by the kinase
domain. Biochemical and biophysical evidence suggest that the oncogenic
mutations impact the conformational dynamics of the enzyme.
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