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PDBsum entry 3fdn
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Contents |
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* Residue conservation analysis
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PDB id:
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Transferase
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Title:
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Structure-based drug design of novel aurora kinase a inhibitors: structure basis for potency and specificity
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Structure:
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Serine/threonine-protein kinase 6. Chain: a. Fragment: catalytic domain. Synonym: aurora kinase a, aurora-a, serine/threonine kinase 15, aurora/ipl1-related kinase 1, aurora-related kinase 1, hark1, breast tumor-amplified kinase. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
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Resolution:
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1.90Å
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R-factor:
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0.231
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R-free:
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0.287
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Authors:
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J.S.Leou,J.S.Wu,M.S.Coumar,P.Shukla,H.P.Hsieh,S.Y.Wu
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Key ref:
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M.S.Coumar
et al.
(2009).
Structure-based drug design of novel Aurora kinase A inhibitors: structural basis for potency and specificity.
J Med Chem,
52,
1050-1062.
PubMed id:
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Date:
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26-Nov-08
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Release date:
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15-Sep-09
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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.
261 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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J Med Chem
52:1050-1062
(2009)
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PubMed id:
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Structure-based drug design of novel Aurora kinase A inhibitors: structural basis for potency and specificity.
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M.S.Coumar,
J.S.Leou,
P.Shukla,
J.S.Wu,
A.K.Dixit,
W.H.Lin,
C.Y.Chang,
T.W.Lien,
U.K.Tan,
C.H.Chen,
J.T.Hsu,
Y.S.Chao,
S.Y.Wu,
H.P.Hsieh.
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ABSTRACT
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Aurora kinases have emerged as attractive targets for the design of anticancer
drugs. Through structure-based virtual screening, novel pyrazole hit 8a was
identified as Aurora kinase A inhibitor (IC(50) = 15.1 microM). X-ray cocrystal
structure of 8a in complex with Aurora A protein revealed the C-4 position ethyl
carboxylate side chain as a possible modification site for improving the
potency. On the basis of this insight, bioisosteric replacement of the ester
with amide linkage and changing the ethyl substituent to hydrophobic
3-acetamidophenyl ring led to the identification of 12w with a approximately
450-fold improved Aurora kinase A inhibition potency (IC(50) = 33 nM), compared
to 8a. Compound 12w showed selective inhibition of Aurora A kinase over Aurora
B/C, which might be due to the presence of a unique H-bond interaction between
the 3-acetamido group and the Aurora A nonconserved Thr217 residue, which in
Aurora B/C is Glu and found to sterically clash with the 3-acetamido group in
modeling studies.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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A.Yan,
Y.Chong,
L.Wang,
X.Hu,
and
K.Wang
(2011).
Prediction of biological activity of Aurora-A kinase inhibitors by multilinear regression analysis and support vector machine.
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Bioorg Med Chem Lett,
21,
2238-2243.
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M.S.Coumar,
M.T.Tsai,
C.Y.Chu,
B.J.Uang,
W.H.Lin,
C.Y.Chang,
T.Y.Chang,
J.S.Leou,
C.H.Teng,
J.S.Wu,
M.Y.Fang,
C.H.Chen,
J.T.Hsu,
S.Y.Wu,
Y.S.Chao,
and
H.P.Hsieh
(2010).
Identification, SAR studies, and X-ray co-crystallographic analysis of a novel furanopyrimidine aurora kinase A inhibitor.
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ChemMedChem,
5,
255-267.
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PDB code:
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
code is
shown on the right.
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Links
