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PDBsum entry 3k2l
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References listed in PDB file
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Key reference
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Title
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Structures of down syndrome kinases, Dyrks, Reveal mechanisms of kinase activation and substrate recognition.
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Authors
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M.Soundararajan,
A.K.Roos,
P.Savitsky,
P.Filippakopoulos,
A.N.Kettenbach,
J.V.Olsen,
S.A.Gerber,
J.Eswaran,
S.Knapp,
J.M.Elkins.
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Ref.
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Structure, 2013,
21,
986-996.
[DOI no: ]
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PubMed id
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Abstract
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Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinases (DYRKs) play key
roles in brain development, regulation of splicing, and apoptosis, and are
potential drug targets for neurodegenerative diseases and cancer. We present
crystal structures of one representative member of each DYRK subfamily: DYRK1A
with an ATP-mimetic inhibitor and consensus peptide, and DYRK2 including NAPA
and DH (DYRK homology) box regions. The current activation model suggests that
DYRKs are Ser/Thr kinases that only autophosphorylate the second tyrosine of the
activation loop YxY motif during protein translation. The structures explain the
roles of this tyrosine and of the DH box in DYRK activation and provide a
structural model for DYRK substrate recognition. Phosphorylation of a library of
naturally occurring peptides identified substrate motifs that lack proline in
the P+1 position, suggesting that DYRK1A is not a strictly proline-directed
kinase. Our data also show that DYRK1A wild-type and Y321F mutant retain
tyrosine autophosphorylation activity.
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