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PDBsum entry 4uv7
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596 a.a.
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218 a.a.
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216 a.a.
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PDB id:
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Transferase
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Title:
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The complex structure of extracellular domain of egfr and gc1118a
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Structure:
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Epidermal growth factor receptor. Chain: a. Fragment: extracellular domain, unp residues 25-645. Synonym: proto-oncogenE C-erbb-1, receptor tyrosine-protein kinase erbb-1, epidermal growth factor receptor 1. Engineered: yes. Gc1118a. Chain: h. Engineered: yes.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_cell_line: cho.
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Resolution:
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2.10Å
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R-factor:
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0.204
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R-free:
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0.248
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Authors:
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J.H.Yoo,H.S.Cho
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Key ref:
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Y.Lim
et al.
(2016).
GC1118, an Anti-EGFR Antibody with a Distinct Binding Epitope and Superior Inhibitory Activity against High-Affinity EGFR Ligands.
Mol Cancer Ther,
15,
251-263.
PubMed id:
DOI:
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Date:
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05-Aug-14
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Release date:
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14-Oct-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.
596 a.a.
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Enzyme class:
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Chain A:
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]
Bound ligand (Het Group name = )
matches with 41.38% similarity
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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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Mol Cancer Ther
15:251-263
(2016)
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PubMed id:
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GC1118, an Anti-EGFR Antibody with a Distinct Binding Epitope and Superior Inhibitory Activity against High-Affinity EGFR Ligands.
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Y.Lim,
J.Yoo,
M.S.Kim,
M.Hur,
E.H.Lee,
H.S.Hur,
J.C.Lee,
S.N.Lee,
T.W.Park,
K.Lee,
K.H.Chang,
K.Kim,
Y.Kang,
K.W.Hong,
S.H.Kim,
Y.G.Kim,
Y.Yoon,
D.H.Nam,
H.Yang,
D.G.Kim,
H.S.Cho,
J.Won.
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ABSTRACT
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The EGFR-targeted monoclonal antibodies are a valid therapeutic strategy for
patients with metastatic colorectal cancer (mCRC). However, only a small subset
of mCRC patients has therapeutic benefits and there are high demands for EGFR
therapeutics with a broader patient pool and more potent efficacy. In this
study, we report GC1118 exhibiting a different character in terms of binding
epitope, affinity, mode of action, and efficacy from other anti-EGFR antibodies.
Structural analysis of the EGFR-GC1118 crystal complex revealed that GC1118
recognizes linear, discrete N-terminal epitopes of domain III of EGFR, critical
for EGF binding but not overlapping with those of other EGFR-targeted
antibodies. GC1118 exhibited superior inhibitory activity against high-affinity
EGFR ligands in terms of EGFR binding, triggering EGFR signaling, and
proliferation compared with cetuximab and panitumumab. EGFR signaling driven by
low-affinity ligands, on the contrary, was well inhibited by all the antibodies
tested. GC1118 demonstrated robust antitumor activity in tumor xenografts with
elevated expression of high-affinity ligands in vivo, whereas cetuximab did not.
Considering the significant role of high-affinity EGFR ligands in modulating
tumor microenvironment and inducing resistance to various cancer therapeutics,
our study suggests a potential therapeutic advantage of GC1118 in terms of
efficacy and a range of benefited patient pool. Mol Cancer Ther; 15(2); 251-63.
©2015 AACR.
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Links
