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PDBsum entry 5ibs
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References listed in PDB file
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Key reference
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Title
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Structural and functional consequences of three cancer-Associated mutations of the oncogenic phosphatase shp2.
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Authors
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J.R.Larochelle,
M.Fodor,
X.Xu,
I.Durzynska,
L.Fan,
T.Stams,
H.M.Chan,
M.J.Lamarche,
R.Chopra,
P.Wang,
P.D.Fortin,
M.G.Acker,
S.C.Blacklow.
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Ref.
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Biochemistry, 2016,
55,
2269-2277.
[DOI no: ]
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PubMed id
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Abstract
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The proto-oncogene PTPN11 encodes a cytoplasmic protein tyrosine phosphatase,
SHP2, which is required for normal development and sustained activation of the
Ras-MAPK signaling pathway. Germline mutations in SHP2 cause developmental
disorders, and somatic mutations have been identified in childhood and adult
cancers and drive leukemia in mice. Despite our knowledge of the PTPN11
variations associated with pathology, the structural and functional consequences
of many disease-associated mutants remain poorly understood. Here, we combine
X-ray crystallography, small-angle X-ray scattering, and biochemistry to
elucidate structural and mechanistic features of three cancer-associated SHP2
variants harboring single point mutations within the N-SH2:PTP interdomain
autoinhibitory interface. Our findings directly compare the impact of each
mutation on autoinhibition of the phosphatase and advance the development of
structure-guided and mutation-specific SHP2 therapies.
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