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PDBsum entry 3ds6
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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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P38 complex with a phthalazine inhibitor
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Structure:
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Mitogen-activated protein kinase 14. Chain: a, b, c, d. Fragment: human p38 kinase. 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. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: mapk14, csbp, csbp1, csbp2, cspb1, mxi2. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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2.90Å
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R-factor:
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0.228
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R-free:
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0.319
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Authors:
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B.Herberich,R.Syed,V.Li,D.Grosfeld
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Key ref:
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B.Herberich
et al.
(2008).
Discovery of highly selective and potent p38 inhibitors based on a phthalazine scaffold.
J Med Chem,
51,
6271-6279.
PubMed id:
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Date:
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11-Jul-08
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Release date:
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07-Oct-08
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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.
343 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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J Med Chem
51:6271-6279
(2008)
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PubMed id:
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Discovery of highly selective and potent p38 inhibitors based on a phthalazine scaffold.
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B.Herberich,
G.Q.Cao,
P.P.Chakrabarti,
J.R.Falsey,
L.Pettus,
R.M.Rzasa,
A.B.Reed,
A.Reichelt,
K.Sham,
M.Thaman,
R.P.Wurz,
S.Xu,
D.Zhang,
F.Hsieh,
M.R.Lee,
R.Syed,
V.Li,
D.Grosfeld,
M.H.Plant,
B.Henkle,
L.Sherman,
S.Middleton,
L.M.Wong,
A.S.Tasker.
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ABSTRACT
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Investigations into the structure-activity relationships (SAR) of a series of
phthalazine-based inhibitors of p38 are described. These efforts originated from
quinazoline 1 and through rational design led to the development of a series of
orally bioavailable, potent, and selective inhibitors. Kinase selectivity was
achieved by exploiting a collection of interactions with p38alpha including
close contact to Ala157, occupation of the hydrophobic gatekeeper pocket, and a
residue flip with Gly110. Substitutions on the phthalazine influenced the
pharmacokinetic properties, of which compound 16 displayed the most desirable
profile. Oral dosing (0.03 mg/kg) of 16 in rats 1 h prior to LPS challenge gave
a >50% decrease in TNFalpha production.
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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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M.Soth,
S.Abbot,
A.Abubakari,
N.Arora,
H.Arzeno,
R.Billedeau,
N.Dewdney,
K.Durkin,
S.Frauchiger,
M.Ghate,
D.M.Goldstein,
R.J.Hill,
A.Kuglstatter,
F.Li,
B.Loe,
K.McCaleb,
J.McIntosh,
E.Papp,
J.Park,
M.Stahl,
M.L.Sung,
R.Suttman,
D.C.Swinney,
P.Weller,
B.Wong,
H.Zecic,
and
T.Gabriel
(2011).
3-Amino-pyrazolo[3,4-d]pyrimidines as p38α kinase inhibitors: Design and development to a highly selective lead.
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Bioorg Med Chem Lett,
21,
3452-3456.
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L.K.Chico,
L.J.Van Eldik,
and
D.M.Watterson
(2009).
Targeting protein kinases in central nervous system disorders.
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Nat Rev Drug Discov,
8,
892-909.
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L.R.Coulthard,
D.E.White,
D.L.Jones,
M.F.McDermott,
and
S.A.Burchill
(2009).
p38(MAPK): stress responses from molecular mechanisms to therapeutics.
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Trends Mol Med,
15,
369-379.
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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.
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Links
