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PDBsum entry 1m14
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-Anilinoquinazoline inhibitor.
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Authors
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J.Stamos,
M.X.Sliwkowski,
C.Eigenbrot.
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Ref.
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J Biol Chem, 2002,
277,
46265-46272.
[DOI no: ]
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PubMed id
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Abstract
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The crystal structure of the kinase domain from the epidermal growth factor
receptor (EGFRK) including forty amino acids from the carboxyl-terminal tail has
been determined to 2.6-A resolution, both with and without an EGFRK-specific
inhibitor currently in Phase III clinical trials as an anti-cancer agent,
erlotinib (OSI-774, CP-358,774, Tarceva(TM)). The EGFR family members are
distinguished from all other known receptor tyrosine kinases in possessing
constitutive kinase activity without a phosphorylation event within their kinase
domains. Despite its lack of phosphorylation, we find that the EGFRK activation
loop adopts a conformation similar to that of the phosphorylated active form of
the kinase domain from the insulin receptor. Surprisingly, key residues of a
putative dimerization motif lying between the EGFRK domain and carboxyl-terminal
substrate docking sites are found in close contact with the kinase domain.
Significant intermolecular contacts involving the carboxyl-terminal tail are
discussed with respect to receptor oligomerization.
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Figure 2.
Fig. 2. Activation loops. The close structural
correspondence between the EGFRK A-loop (blue) and the A-loop
from the phosphorylated form of the insulin receptor kinase (33)
(gold) is shown. The hydrophobic interaction between Lys836 and
Tyr845 almost exactly reprises that between Arg1155 and Tyr1163
of p-IRK (underlined). The presence of four glutamate residues
in this part of EGFRK has been suggested as a cause for its
intrinsic catalytic activity.
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Figure 4.
Fig. 4. The LVI tripeptide segment of EGFRK is found in
close association with the C-lobe. A solvent-accessible surface
from EGFRK with LVI removed is depicted. Residue Leu955, the
most important as gauged by mutagenesis studies, is found within
what in its absence would be a hydrophobic pit.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2002,
277,
46265-46272)
copyright 2002.
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