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PDBsum entry 4zjv
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Transferase/inhibitor
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PDB id
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4zjv
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PDB id:
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Transferase/inhibitor
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Title:
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Crystal structure of egfr kinase domain in complex with mitogen- inducible gene 6 protein
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Structure:
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Epidermal growth factor receptor. Chain: a, b. Fragment: kinase domain (unp residues 695-1022). Synonym: proto-oncogenE C-erbb-1,receptor tyrosine-protein kinase erbb-1. Engineered: yes. Erbb receptor feedback inhibitor 1. Chain: c, d. Fragment: unp residues 330-399.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: egfr, erbb, erbb1, her1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Gene: errfi1, mig6. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Resolution:
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2.70Å
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R-factor:
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0.181
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R-free:
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0.232
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Authors:
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M.J.Eck,E.Park,B.Lee
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Key ref:
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E.Park
et al.
(2015).
Structure and mechanism of activity-based inhibition of the EGF receptor by Mig6.
Nat Struct Biol,
22,
703-711.
PubMed id:
DOI:
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Date:
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29-Apr-15
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Release date:
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12-Aug-15
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PROCHECK
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Headers
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References
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P00533
(EGFR_HUMAN) -
Epidermal growth factor receptor from Homo sapiens
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Seq:
Struc:
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1210 a.a.
282 a.a.
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Enzyme class:
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Chains A, B:
E.C.2.7.10.1
- receptor protein-tyrosine kinase.
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Reaction:
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L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
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L-tyrosyl-[protein]
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+
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ATP
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=
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O-phospho-L-tyrosyl-[protein]
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+
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ADP
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Nat Struct Biol
22:703-711
(2015)
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PubMed id:
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Structure and mechanism of activity-based inhibition of the EGF receptor by Mig6.
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E.Park,
N.Kim,
S.B.Ficarro,
Y.Zhang,
B.I.Lee,
A.Cho,
K.Kim,
A.K.Park,
W.Y.Park,
B.Murray,
M.Meyerson,
R.Beroukhim,
J.A.Marto,
J.Cho,
M.J.Eck.
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ABSTRACT
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Mig6 is a feedback inhibitor that directly binds, inhibits and drives
internalization of ErbB-family receptors. Mig6 selectively targets activated
receptors. Here we found that the epidermal growth factor receptor (EGFR)
phosphorylates Mig6 on Y394 and that this phosphorylation is primed by prior
phosphorylation of an adjacent residue, Y395, by Src. Crystal structures of
human EGFR-Mig6 complexes reveal the structural basis for enhanced
phosphorylation of primed Mig6 and show how Mig6 rearranges after
phosphorylation by EGFR to effectively irreversibly inhibit the same receptor
that catalyzed its phosphorylation. This dual phosphorylation site allows Mig6
to inactivate EGFR in a manner that requires activation of the target receptor
and that can be modulated by Src. Loss of Mig6 is a driving event in human
cancer; analysis of 1,057 gliomas reveals frequent focal deletions of ERRFI1,
the gene that encodes Mig6, in EGFR-amplified glioblastomas.
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