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PDBsum entry 5dpv
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PDB id:
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Transferase
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Title:
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Aurora a kinase in complex with aa35 and jnj-7706621 in space group p6122
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Structure:
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Aurora kinase a. Chain: a. Fragment: unp residues 126-390. Synonym: aurora 2,aurora/ipl1-related kinase 1,hark1,breast tumor- amplified kinase,serine/threonine-protein kinase 15,serine/threonine- protein kinase 6,serine/threonine-protein kinase aurora-a. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: aurka, aik, airk1, ark1, aura, ayk1, btak, iak1, stk15, stk6. Expressed in: escherichia coli. Expression_system_taxid: 469008. Expression_system_variant: pubs520.
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Resolution:
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2.29Å
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R-factor:
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0.225
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R-free:
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0.280
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Authors:
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M.Janecek,M.Rossmann,P.Sharma,A.Emery,G.J.Mckenzie,D.J.Huggins, S.Stockwell,J.A.Stokes,E.G.Almeida,B.Hardwick,A.J.Narvaez,M.Hyvonen, D.R.Spring,A.R.Venkitaraman
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Key ref:
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M.Janeček
et al.
(2016).
Allosteric modulation of AURKA kinase activity by a small-molecule inhibitor of its protein-protein interaction with TPX2.
Sci Rep,
6,
28528.
PubMed id:
DOI:
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Date:
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14-Sep-15
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Release date:
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20-Jul-16
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PROCHECK
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Headers
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References
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O14965
(AURKA_HUMAN) -
Aurora kinase A from Homo sapiens
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Seq:
Struc:
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403 a.a.
257 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.2.7.11.1
- non-specific serine/threonine protein kinase.
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Reaction:
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1.
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L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H+
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2.
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L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H+
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L-seryl-[protein]
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+
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ATP
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=
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O-phospho-L-seryl-[protein]
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+
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ADP
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+
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H(+)
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L-threonyl-[protein]
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+
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ATP
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=
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O-phospho-L-threonyl-[protein]
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+
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ADP
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Sci Rep
6:28528
(2016)
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PubMed id:
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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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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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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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