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PDBsum entry 5e8d
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Immune system
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PDB id
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5e8d
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Contents |
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43 a.a.
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216 a.a.
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210 a.a.
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References listed in PDB file
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Key reference
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Title
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Epiregulin recognition mechanisms by anti-Epiregulin antibody 9e5: structural, Functional, And molecular dynamics simulation analyses.
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Authors
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Y.Kado,
E.Mizohata,
S.Nagatoishi,
M.Iijima,
K.Shinoda,
T.Miyafusa,
T.Nakayama,
T.Yoshizumi,
A.Sugiyama,
T.Kawamura,
Y.H.Lee,
H.Matsumura,
H.Doi,
H.Fujitani,
T.Kodama,
Y.Shibasaki,
K.Tsumoto,
T.Inoue.
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Ref.
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J Biol Chem, 2016,
291,
2319-2330.
[DOI no: ]
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PubMed id
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Abstract
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Epiregulin (EPR) is a ligand of the epidermal growth factor (EGF) family that
upon binding to its epidermal growth factor receptor (EGFR) stimulates
proliferative signaling, especially in colon cancer cells. Here, we describe the
three-dimensional structure of the EPR antibody (the 9E5(Fab) fragment) in the
presence and absence of EPR. Among the six complementarity-determining regions
(CDRs), CDR1-3 in the light chain and CDR2 in the heavy chain predominantly
recognize EPR. In particular, CDR3 in the heavy chain dramatically moves with
cis-trans isomerization of Pro(103). A molecular dynamics simulation and
mutational analyses revealed that Arg(40) in EPR is a key residue for the
specific binding of 9E5 IgG. From isothermal titration calorimetry analysis, the
dissociation constant was determined to be 6.5 nm. Surface plasmon resonance
analysis revealed that the dissociation rate of 9E5 IgG is extremely slow. The
superimposed structure of 9E5(Fab)·EPR on the known complex structure of
EGF·EGFR showed that the 9E5(Fab) paratope overlaps with Domains I and III on
the EGFR, which reveals that the 9E5(Fab)·EPR complex could not bind to the
EGFR. The 9E5 antibody will also be useful in medicine as a neutralizing
antibody specific for colon cancer.
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