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PDBsum entry 4byj
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PDB id:
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Transferase
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Title:
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Aurora a kinase bound to a highly selective imidazopyridine inhibitor
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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, ark-1, aurora- 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. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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2.75Å
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R-factor:
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0.232
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R-free:
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0.248
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Authors:
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A.Joshi,M.Kosmopoulou,R.Bayliss
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Key ref:
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V.Bavetsias
et al.
(2013).
Aurora isoform selectivity: design and synthesis of imidazo[4,5-b]pyridine derivatives as highly selective inhibitors of Aurora-A kinase in cells.
J Med Chem,
56,
9122-9135.
PubMed id:
DOI:
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Date:
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19-Jul-13
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Release date:
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20-Nov-13
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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.
246 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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J Med Chem
56:9122-9135
(2013)
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PubMed id:
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Aurora isoform selectivity: design and synthesis of imidazo[4,5-b]pyridine derivatives as highly selective inhibitors of Aurora-A kinase in cells.
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V.Bavetsias,
A.Faisal,
S.Crumpler,
N.Brown,
M.Kosmopoulou,
A.Joshi,
B.Atrash,
Y.Pérez-Fuertes,
J.A.Schmitt,
K.J.Boxall,
R.Burke,
C.Sun,
S.Avery,
K.Bush,
A.Henley,
F.I.Raynaud,
P.Workman,
R.Bayliss,
S.Linardopoulos,
J.Blagg.
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ABSTRACT
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Aurora-A differs from Aurora-B/C at three positions in the ATP-binding pocket
(L215, T217, and R220). Exploiting these differences, crystal structures of
ligand-Aurora protein interactions formed the basis of a design principle for
imidazo[4,5-b]pyridine-derived Aurora-A-selective inhibitors. Guided by a
computational modeling approach, appropriate C7-imidazo[4,5-b]pyridine
derivatization led to the discovery of highly selective inhibitors, such as
compound 28c, of Aurora-A over Aurora-B. In HCT116 human colon carcinoma cells,
28c and 40f inhibited the Aurora-A L215R and R220K mutants with IC50 values
similar to those seen for the Aurora-A wild type. However, the Aurora-A T217E
mutant was significantly less sensitive to inhibition by 28c and 40f compared to
the Aurora-A wild type, suggesting that the T217 residue plays a critical role
in governing the observed isoform selectivity for Aurora-A inhibition. These
compounds are useful small-molecule chemical tools to further explore the
function of Aurora-A in cells.
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Links
