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PDBsum entry 4jvg
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Transferase/transferase inhibitor
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PDB id
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4jvg
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References listed in PDB file
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Key reference
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Title
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Inhibitors that stabilize a closed raf kinase domain conformation induce dimerization.
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Authors
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H.Lavoie,
N.Thevakumaran,
G.Gavory,
J.J.Li,
A.Padeganeh,
S.Guiral,
J.Duchaine,
D.Y.Mao,
M.Bouvier,
F.Sicheri,
M.Therrien.
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Ref.
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Nat Chem Biol, 2013,
9,
428-436.
[DOI no: ]
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PubMed id
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Abstract
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RAF kinases have a prominent role in cancer. Their mode of activation is complex
but critically requires dimerization of their kinase domains. Unexpectedly,
several ATP-competitive RAF inhibitors were recently found to promote
dimerization and transactivation of RAF kinases in a RAS-dependent manner and,
as a result, undesirably stimulate RAS/ERK pathway-mediated cell growth. The
mechanism by which these inhibitors induce RAF kinase domain dimerization
remains unclear. Here we describe bioluminescence resonance energy
transfer-based biosensors for the extended RAF family that enable the detection
of RAF dimerization in living cells. Notably, we demonstrate the utility of
these tools for profiling kinase inhibitors that selectively modulate RAF
dimerization and for probing structural determinants of RAF dimerization in
vivo. Our findings, which seem generalizable to other kinase families
allosterically regulated by kinase domain dimerization, suggest a model whereby
ATP-competitive inhibitors mediate RAF dimerization by stabilizing a rigid
closed conformation of the kinase domain.
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