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PDBsum entry 5dpv
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References listed in PDB file
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Key reference
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Title
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Allosteric modulation of aurka kinase activity by a small-Molecule inhibitor of its protein-Protein interaction with tpx2.
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Authors
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M.Janeček,
M.Rossmann,
P.Sharma,
A.Emery,
D.J.Huggins,
S.R.Stockwell,
J.E.Stokes,
Y.S.Tan,
E.G.Almeida,
B.Hardwick,
A.J.Narvaez,
M.Hyvönen,
D.R.Spring,
G.J.Mckenzie,
A.R.Venkitaraman.
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Ref.
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Sci Rep, 2016,
6,
28528.
[DOI no: ]
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PubMed id
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Abstract
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The essential mitotic kinase Aurora A (AURKA) is controlled during cell cycle
progression via two distinct mechanisms. Following activation loop
autophosphorylation early in mitosis when it localizes to centrosomes, AURKA is
allosterically activated on the mitotic spindle via binding to the
microtubule-associated protein, TPX2. Here, we report the discovery of AurkinA,
a novel chemical inhibitor of the AURKA-TPX2 interaction, which acts via an
unexpected structural mechanism to inhibit AURKA activity and mitotic
localization. In crystal structures, AurkinA binds to a hydrophobic pocket (the
'Y pocket') that normally accommodates a conserved Tyr-Ser-Tyr motif from TPX2,
blocking the AURKA-TPX2 interaction. AurkinA binding to the Y- pocket induces
structural changes in AURKA that inhibit catalytic activity in vitro and in
cells, without affecting ATP binding to the active site, defining a novel
mechanism of allosteric inhibition. Consistent with this mechanism, cells
exposed to AurkinA mislocalise AURKA from mitotic spindle microtubules. Thus,
our findings provide fresh insight into the catalytic mechanism of AURKA, and
identify a key structural feature as the target for a new class of dual-mode
AURKA inhibitors, with implications for the chemical biology and selective
therapeutic targeting of structurally related kinases.
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