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PDBsum entry 5hic
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Transferase/transferase inhibitor
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PDB id
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5hic
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References listed in PDB file
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Key reference
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Title
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Activation mechanism of oncogenic deletion mutations in braf, Egfr, And her2.
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Authors
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S.A.Foster,
D.M.Whalen,
A.Özen,
M.J.Wongchenko,
J.Yin,
I.Yen,
G.Schaefer,
J.D.Mayfield,
J.Chmielecki,
P.J.Stephens,
L.A.Albacker,
Y.Yan,
K.Song,
G.Hatzivassiliou,
C.Eigenbrot,
C.Yu,
A.S.Shaw,
G.Manning,
N.J.Skelton,
S.G.Hymowitz,
S.Malek.
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Ref.
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Cancer Cell, 2016,
29,
477-493.
[DOI no: ]
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PubMed id
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Abstract
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Activating mutations in protein kinases drive many cancers. While how recurring
point mutations affect kinase activity has been described, the effect of
in-frame deletions is not well understood. We show that oncogenic deletions
within the β3-αC loop of HER2 and BRAF are analogous to the recurrent EGFR
exon 19 deletions. We identify pancreatic carcinomas with BRAF deletions
mutually exclusive with KRAS mutations. Crystal structures of BRAF deletions
reveal the truncated loop restrains αC in an active "in"
conformation, imparting resistance to inhibitors like vemurafenib that bind the
αC "out" conformation. Characterization of loop length explains the
prevalence of five amino acid deletions in BRAF, EGFR, and HER2 and highlights
the importance of this region for kinase activity and inhibitor efficacy.
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