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PDBsum entry 2gs7
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References listed in PDB file
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Key reference
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Title
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An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor.
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Authors
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X.Zhang,
J.Gureasko,
K.Shen,
P.A.Cole,
J.Kuriyan.
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Ref.
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Cell, 2006,
125,
1137-1149.
[DOI no: ]
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PubMed id
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Abstract
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The mechanism by which the epidermal growth factor receptor (EGFR) is activated
upon dimerization has eluded definition. We find that the EGFR kinase domain can
be activated by increasing its local concentration or by mutating a leucine
(L834R) in the activation loop, the phosphorylation of which is not required for
activation. This suggests that the kinase domain is intrinsically autoinhibited,
and an intermolecular interaction promotes its activation. Using further
mutational analysis and crystallography we demonstrate that the autoinhibited
conformation of the EGFR kinase domain resembles that of Src and
cyclin-dependent kinases (CDKs). EGFR activation results from the formation of
an asymmetric dimer in which the C-terminal lobe of one kinase domain plays a
role analogous to that of cyclin in activated CDK/cyclin complexes. The
CDK/cyclin-like complex formed by two kinase domains thus explains the
activation of EGFR-family receptors by homo- or heterodimerization.
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Figure 1.
Figure 1. Ligand-Induced Dimerization of EGFR and Active
and Inactive States of Its Kinase Domain
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Figure 4.
Figure 4. The Asymmetric CDK/Cyclin-like Crystallographic
Dimer of the EGFR Kinase Domain
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The above figures are
reprinted
by permission from Cell Press:
Cell
(2006,
125,
1137-1149)
copyright 2006.
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