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PDBsum entry 4ztq
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PDB id:
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Transferase
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Title:
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Human aurora a catalytic domain bound to fk932
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Structure:
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Aurora kinase a. Chain: a. Fragment: residues 122-403. 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
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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: 562
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Resolution:
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2.80Å
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R-factor:
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0.203
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R-free:
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0.246
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Authors:
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M.J.Marcaida,F.Kilchmann,T.Schick,J.L.Reymond
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Key ref:
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F.Kilchmann
et al.
(2016).
Discovery of a Selective Aurora A Kinase Inhibitor by Virtual Screening.
J Med Chem,
59,
7188-7211.
PubMed id:
DOI:
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Date:
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14-May-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.
247 a.a.
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Key: |
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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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J Med Chem
59:7188-7211
(2016)
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PubMed id:
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Discovery of a Selective Aurora A Kinase Inhibitor by Virtual Screening.
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F.Kilchmann,
M.J.Marcaida,
S.Kotak,
T.Schick,
S.D.Boss,
M.Awale,
P.Gönczy,
J.L.Reymond.
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ABSTRACT
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Here we report the discovery of a selective inhibitor of Aurora A, a key
regulator of cell division and potential anticancer target. We used the atom
category extended ligand overlap score (xLOS), a 3D ligand-based virtual
screening method recently developed in our group, to select 437 shape and
pharmacophore analogs of reference kinase inhibitors. Biochemical screening
uncovered two inhibitor series with scaffolds unprecedented among kinase
inhibitors. One of them was successfully optimized by structure-based design to
a potent Aurora A inhibitor (IC50 = 2 nM) with very high kinome selectivity for
Aurora kinases. This inhibitor locks Aurora A in an inactive conformation and
disrupts binding to its activator protein TPX2, which impairs Aurora A
localization at the mitotic spindle and induces cell division defects. This
phenotype can be rescued by inhibitor-resistant Aurora A mutants. The inhibitor
furthermore does not induce Aurora B specific effects in cells.
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Links
