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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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References listed in PDB file
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Key reference
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Title
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Molecular mechanism of ssr128129e, An extracellularly acting, Small-Molecule, Allosteric inhibitor of fgf receptor signaling.
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Authors
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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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Ref.
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Cancer Cell, 2013,
23,
489-501.
[DOI no: ]
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PubMed id
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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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