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PDBsum entry 5e8v
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References listed in PDB file
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Key reference
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Title
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Crystal structures of apo and inhibitor-Bound tgfβr2 kinase domain: insights into tgfβr isoform selectivity.
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Authors
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A.J.Tebben,
M.Ruzanov,
M.Gao,
D.Xie,
S.E.Kiefer,
C.Yan,
J.A.Newitt,
L.Zhang,
K.Kim,
H.Lu,
L.M.Kopcho,
S.Sheriff.
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Ref.
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Acta Crystallogr D Struct Biol, 2016,
72,
658-674.
[DOI no: ]
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PubMed id
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Abstract
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The cytokine TGF-β modulates a number of cellular activities and plays a
critical role in development, hemostasis and physiology, as well as in diseases
including cancer and fibrosis. TGF-β signals through two transmembrane
serine/threonine kinase receptors: TGFβR1 and TGFβR2. Multiple structures of
the TGFβR1 kinase domain are known, but the structure of TGFβR2 remains
unreported. Wild-type TGFβR2 kinase domain was refractory to crystallization,
leading to the design of two mutated constructs: firstly, a TGFβR1 chimeric
protein with seven ATP-site residues mutated to their counterparts in TGFβR2,
and secondly, a reduction of surface entropy through mutation of six charged
residues on the surface of the TGFβR2 kinase domain to alanines. These yielded
apo and inhibitor-bound crystals that diffracted to high resolution
(<2 Å). Comparison of these structures with those of TGFβR1 reveal shared
ligand contacts as well as differences in the ATP-binding sites, suggesting
strategies for the design of pan and selective TGFβR inhibitors.
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