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PDBsum entry 6ekd
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PDB id:
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Transferase
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Title:
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Crystal structure of jnk3 in complex with a pyridinylimidazole inhibitor
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Structure:
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Mitogen-activated protein kinase 10. Chain: a. Synonym: mapk 10,map kinase p49 3f12,stress-activated protein kinase 1b,sapk1b,stress-activated protein kinase jnk3,c-jun n-terminal kinase 3. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: mapk10, jnk3, jnk3a, prkm10, sapk1b. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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2.10Å
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R-factor:
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0.208
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R-free:
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0.259
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Authors:
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J.T.Macedo,T.Stehle,B.S.Blaum
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Key ref:
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F.Ansideri
et al.
(2018).
Structural Optimization of a Pyridinylimidazole Scaffold: Shifting the Selectivity from p38α Mitogen-Activated Protein Kinase to c-Jun N-Terminal Kinase 3.
ACS Omega,
3,
7809-7831.
PubMed id:
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Date:
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26-Sep-17
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Release date:
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08-Aug-18
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PROCHECK
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Headers
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References
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P53779
(MK10_HUMAN) -
Mitogen-activated protein kinase 10 from Homo sapiens
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Seq:
Struc:
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464 a.a.
325 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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Enzyme class:
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E.C.2.7.11.24
- mitogen-activated 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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ACS Omega
3:7809-7831
(2018)
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PubMed id:
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Structural Optimization of a Pyridinylimidazole Scaffold: Shifting the Selectivity from p38α Mitogen-Activated Protein Kinase to c-Jun N-Terminal Kinase 3.
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F.Ansideri,
J.T.Macedo,
M.Eitel,
A.El-Gokha,
D.S.Zinad,
C.Scarpellini,
M.Kudolo,
D.Schollmeyer,
F.M.Boeckler,
B.S.Blaum,
S.A.Laufer,
P.Koch.
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ABSTRACT
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Starting from known p38α mitogen-activated protein kinase (MAPK) inhibitors, a
series of inhibitors of the c-Jun N-terminal kinase (JNK) 3 was obtained.
Altering the substitution pattern of the pyridinylimidazole scaffold proved to
be effective in shifting the inhibitory activity from the original target p38α
MAPK to the closely related JNK3. In particular, a significant improvement for
JNK3 selectivity could be achieved by addressing the hydrophobic region I with a
small methyl group. Furthermore, additional structural modifications permitted
to explore structure-activity relationships. The most potent inhibitor
4-(4-methyl-2-(methylthio)-1H-imidazol-5-yl)-N-(4-morpholinophenyl)pyridin-2-amine
showed an IC50 value for the JNK3 in the low triple digit nanomolar
range and its binding mode was confirmed by X-ray crystallography.
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