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PDBsum entry 6cpm
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Signaling protein
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PDB id
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6cpm
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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 characterization of ubiquitin variant inhibitors of usp15.
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Authors
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J.Teyra,
A.U.Singer,
F.W.Schmitges,
P.Jaynes,
S.Kit leng lui,
M.J.Polyak,
N.Fodil,
J.R.Krieger,
J.Tong,
C.Schwerdtfeger,
B.B.Brasher,
D.F.J.Ceccarelli,
J.Moffat,
F.Sicheri,
M.F.Moran,
P.Gros,
P.J.A.Eichhorn,
M.Lenter,
G.Boehmelt,
S.S.Sidhu.
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Ref.
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Structure, 2019,
27,
590.
[DOI no: ]
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PubMed id
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Abstract
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The multi-domain deubiquitinase USP15 regulates diverse eukaryotic processes and
has been implicated in numerous diseases. We developed ubiquitin variants (UbVs)
that targeted either the catalytic domain or each of three adaptor domains in
USP15, including the N-terminal DUSP domain. We also designed a linear dimer
(diUbV), which targeted the DUSP and catalytic domains, and exhibited enhanced
specificity and more potent inhibition of catalytic activity than either UbV
alone. In cells, the UbVs inhibited the deubiquitination of two USP15
substrates, SMURF2 and TRIM25, and the diUbV inhibited the effects of USP15 on
the transforming growth factor β pathway. Structural analyses revealed that
three distinct UbVs bound to the catalytic domain and locked the active site in
a closed, inactive conformation, and one UbV formed an unusual strand-swapped
dimer and bound two DUSP domains simultaneously. These inhibitors will enable
the study of USP15 function in oncology, neurology, immunology, and inflammation.
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