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PDBsum entry 4j23
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Signaling protein/transferase
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PDB id
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4j23
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PDB id:
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| Name: |
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Signaling protein/transferase
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Title:
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Low resolution crystal structure of the fgfr2d2d3/fgf1/sr128545 complex
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Structure:
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Fibroblast growth factor receptor 2. Chain: a. Fragment: unp residues 147-366. Synonym: fgfr-2, k-sam, kgfr, keratinocyte growth factor receptor. Engineered: yes. Fibroblast growth factor 1. Chain: b. Fragment: unp residues 21-155. Synonym: fgf-1, acidic fibroblast growth factor, afgf, endothelial
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: bek, fgfr2, kgfr, ksam. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: fgf1, fgfa. Expression_system_taxid: 562
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Resolution:
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3.88Å
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R-factor:
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0.324
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R-free:
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0.384
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Authors:
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D.Kudlinzki,K.Saxena,S.Sreeramulu,U.Schieborr,M.Dreyer,H.Schreuder, H.Schwalbe
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Key ref:
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C.Herbert
et al.
(2013).
Molecular mechanism of SSR128129E, an extracellularly acting, small-molecule, allosteric inhibitor of FGF receptor signaling.
Cancer Cell,
23,
489-501.
PubMed id:
DOI:
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Date:
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04-Feb-13
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Release date:
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19-Feb-14
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PROCHECK
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Headers
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References
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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]
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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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Cancer Cell
23:489-501
(2013)
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PubMed id:
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Molecular mechanism of SSR128129E, an extracellularly acting, small-molecule, allosteric inhibitor of FGF receptor signaling.
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C.Herbert,
U.Schieborr,
K.Saxena,
J.Juraszek,
F.De Smet,
C.Alcouffe,
M.Bianciotto,
G.Saladino,
D.Sibrac,
D.Kudlinzki,
S.Sreeramulu,
A.Brown,
P.Rigon,
J.P.Herault,
G.Lassalle,
T.L.Blundell,
F.Rousseau,
A.Gils,
J.Schymkowitz,
P.Tompa,
J.M.Herbert,
P.Carmeliet,
F.L.Gervasio,
H.Schwalbe,
F.Bono.
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ABSTRACT
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The fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR)
signaling network plays an important role in cell growth, survival,
differentiation, and angiogenesis. Deregulation of FGFR signaling can lead to
cancer development. Here, we report an FGFR inhibitor, SSR128129E (SSR), that
binds to the extracellular part of the receptor. SSR does not compete with FGF
for binding to FGFR but inhibits FGF-induced signaling linked to FGFR
internalization in an allosteric manner, as shown by crystallography studies,
nuclear magnetic resonance, Fourier transform infrared spectroscopy, molecular
dynamics simulations, free energy calculations, structure-activity relationship
analysis, and FGFR mutagenesis. Overall, SSR is a small molecule allosteric
inhibitor of FGF/FGFR signaling, acting via binding to the extracellular part of
the FGFR.
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