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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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PDB id:
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| Name: |
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Transferase/transferase inhibitor
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Title:
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B-raf kinase in complex with birb796
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Structure:
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Serine/threonine-protein kinase b-raf. Chain: b, a, c, d. Fragment: kinase domain. Synonym: proto-oncogene b-raf, p94, v-raf murine sarcoma viral oncogene homolog b1. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: braf, braf1, rafb1. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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3.09Å
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R-factor:
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0.235
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R-free:
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0.295
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Authors:
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H.Lavoie,N.Thevakumaran,G.Gavory,J.Li,A.Padeganeh,S.Guiral, J.Duchaine,D.Y.L.Mao,M.Bouvier,F.Sicheri,M.Therrien
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Key ref:
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H.Lavoie
et al.
(2013).
Inhibitors that stabilize a closed RAF kinase domain conformation induce dimerization.
Nat Chem Biol,
9,
428-436.
PubMed id:
DOI:
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Date:
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25-Mar-13
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Release date:
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29-May-13
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PROCHECK
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Headers
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References
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P15056
(BRAF_HUMAN) -
Serine/threonine-protein kinase B-raf from Homo sapiens
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Seq:
Struc:
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766 a.a.
259 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 15 residue positions (black
crosses)
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Enzyme class:
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E.C.2.7.11.1
- non-specific serine/threonine protein kinase.
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Reaction:
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1.
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L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H+
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2.
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L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H+
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L-seryl-[protein]
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+
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ATP
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=
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O-phospho-L-seryl-[protein]
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+
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ADP
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+
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H(+)
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L-threonyl-[protein]
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+
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ATP
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=
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O-phospho-L-threonyl-[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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Nat Chem Biol
9:428-436
(2013)
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PubMed id:
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Inhibitors that stabilize a closed RAF kinase domain conformation induce dimerization.
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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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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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Links
