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PDBsum entry 4wv1
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Transferase/immune system
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PDB id
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4wv1
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Contents |
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98 a.a.
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224 a.a.
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214 a.a.
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PDB id:
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Transferase/immune system
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Title:
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Crystal structure of the fgfr2 d2 domain in complex with fab 2b.1.3
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Structure:
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Fibroblast growth factor receptor 2. Chain: f, c. Fragment: unp residues 153-251. Synonym: fgfr-2,k-sam,kgfr,keratinocyte growth factor receptor. Engineered: yes. Fab heavy chain. Chain: b, e. Engineered: yes. Fab light chain.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: fgfr2, bek, kgfr, ksam. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562
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Resolution:
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2.36Å
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R-factor:
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0.201
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R-free:
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0.244
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Authors:
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Y.Yin,P.J.Carter
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Key ref:
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Y.Yin
et al.
(2015).
Redesigning a Monospecific Anti-FGFR3 Antibody to Add Selectivity for FGFR2 and Expand Antitumor Activity.
Mol Cancer Ther,
14,
2270-2278.
PubMed id:
DOI:
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Date:
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04-Nov-14
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Release date:
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16-Sep-15
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PROCHECK
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Headers
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References
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P21802
(FGFR2_HUMAN) -
Fibroblast growth factor receptor 2 from Homo sapiens
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Seq:
Struc:
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821 a.a.
98 a.a.
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Enzyme class:
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Chains F, C:
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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Mol Cancer Ther
14:2270-2278
(2015)
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PubMed id:
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Redesigning a Monospecific Anti-FGFR3 Antibody to Add Selectivity for FGFR2 and Expand Antitumor Activity.
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Y.Yin,
S.Djakovic,
S.Marsters,
J.Tien,
J.Peng,
J.Tremayne,
G.Lee,
R.M.Neve,
Y.Wu,
M.Merchant,
A.Ashkenazi,
P.J.Carter.
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ABSTRACT
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FGF receptors (FGFR) are attractive candidate targets for cancer therapy because
they are dysregulated in several human malignancies. FGFR2 and FGFR3 can be
inhibited potentially without disrupting adult tissue homeostasis. In contrast,
blocking the closely related FGFR1 and FGFR4, which regulate specific metabolic
functions, carries a greater safety risk. An anti-FGFR3 antibody was redesigned
here to create function-blocking antibodies that bind with dual specificity to
FGFR3 and FGFR2 but spare FGFR1 and FGFR4. R3Mab, a previously developed
monospecific anti-FGFR3 antibody, was modified via structure-guided phage
display and acquired additional binding to FGFR2. The initial variant was
trispecific, binding tightly to FGFR3 and FGFR2 and moderately to FGFR4, while
sparing FGFR1. The X-ray crystallographic structure indicated that the antibody
variant was bound to a similar epitope on FGFR2 as R3Mab on FGFR3. The antibody
was further engineered to decrease FGFR4-binding affinity while retaining
affinity for FGFR3 and FGFR2. The resulting dual-specific antibodies blocked FGF
binding to FGFR3 and FGFR2 and inhibited downstream signaling. Moreover, they
displayed efficacy in mice against human tumor xenografts overexpressing FGFR3
or FGFR2. Thus, a monospecific antibody can be exquisitely tailored to confer or
remove binding to closely related targets to expand and refine therapeutic
potential. Mol Cancer Ther; 14(10); 2270-8. ©2015 AACR.
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