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PDBsum entry 3hp5
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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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Crystal structure of human p38alpha complexed with a pyrimidopyridazinone compound
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Structure:
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Mitogen-activated protein kinase 14. Chain: a. Synonym: mitogen-activated protein kinase p38 alpha, map kinase p38 alpha, cytokine suppressive anti-inflammatory drug-binding protein, csaid-binding protein, csbp, max-interacting protein 2, map kinase mxi2, sapk2a. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: csbp, csbp1, csbp2, cspb1, mapk14, mxi2, thp-1. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Resolution:
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2.30Å
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R-factor:
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0.217
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R-free:
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0.262
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Authors:
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H.-S.Shieh,J.M.Williams,R.A.Stegeman,R.G.Kurumbail
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Key ref:
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S.R.Selness
et al.
(2009).
Discovery of N-substituted pyridinones as potent and selective inhibitors of p38 kinase.
Bioorg Med Chem Lett,
19,
5851-5856.
PubMed id:
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Date:
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03-Jun-09
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Release date:
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29-Sep-09
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PROCHECK
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Headers
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References
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Q16539
(MK14_HUMAN) -
Mitogen-activated protein kinase 14 from Homo sapiens
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Seq:
Struc:
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360 a.a.
330 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.2.7.11.24
- 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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Bioorg Med Chem Lett
19:5851-5856
(2009)
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PubMed id:
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Discovery of N-substituted pyridinones as potent and selective inhibitors of p38 kinase.
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S.R.Selness,
R.V.Devraj,
J.B.Monahan,
T.L.Boehm,
J.K.Walker,
B.Devadas,
R.C.Durley,
R.Kurumbail,
H.Shieh,
L.Xing,
M.Hepperle,
P.V.Rucker,
K.D.Jerome,
A.G.Benson,
L.D.Marrufo,
H.M.Madsen,
J.Hitchcock,
T.J.Owen,
L.Christie,
M.A.Promo,
B.S.Hickory,
E.Alvira,
W.Naing,
R.Blevis-Bal.
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ABSTRACT
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The identification and evolution of a series of potent and selective p38
inhibitors is described. p38 inhibitors based on a N-benzyl pyridinone
high-throughput screening hit were prepared and their SAR explored. Their design
was guided by ligand bound co-crystals of p38alpha. These efforts resulted in
the identification of 12r and 19 as orally active inhibitors of p38 with
significant efficacy in both acute and chronic models of inflammation.
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Links
