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Literature summary for 2.7.11.24 extracted from

  • Fitzgerald, C.E.; Patel, S.B.; Becker, J.W.; Cameron, P.M.; Zaller, D.; Pikounis, V.B.; O'Keefe, S.J.; Scapin, G.
    Structural basis for p38alpha MAP kinase quinazolinone and pyridol-pyrimidine inhibitor specificity (2003), Nat. Struct. Biol., 10, 764-769.
    View publication on PubMed

Cloned(Commentary)

Cloned (Comment) Organism
expression of His-tagged wild-type and mutant p38 isozyme alpha Mus musculus

Crystallization (Commentary)

Crystallization (Comment) Organism
purified p38 isozyme alpha bound to several inhibitors pyridinyl imidazole-type inhibitors, X-ray diffraction structure determination and analysis at 2.1-2.5 A resolution Mus musculus

Protein Variants

Protein Variants Comment Organism
G110A site-directed mutagenesis of isozyme alpha, the mutant shows a slightly decreased Km value for ATP, but unaltered activity compared to the wild-type enzyme, decreased sensitivity for inhibitors compared to the wild-type enzyme Mus musculus
G110D site-directed mutagenesis of isozyme alpha, the mutant shows a decreased Km value for ATP, but unaltered activity compared to the wild-type enzyme, decreased sensitivity for inhibitors compared to the wild-type enzyme Mus musculus

Inhibitors

Inhibitors Comment Organism Structure
1-(2,6-dichloro-phenyl)-5-(2,4-difluoro-phenyl)-7-piperazin-1-yl-3,4-dihydro-1H-quinazolin-2-one highly selective for p38 isozyme alpha wild-type with IC50 of 3.2 nM, the IC50 for mutants G110A and G110D are 37 nM and 56 nM, respectively, no inhibition of JNK3, JNK2, and ERK Mus musculus
1-(2,6-dichloro-phenyl)-5-(2,4-difluoro-phenyl)-7-piperidin-4-yl-3,4-dihydro-1H-quinolin-2-one highly selective for p38 isozyme alpha wild-type with IC50 of 0.74 nM, the IC50 for mutants G110A and G110D are 26 nM and 67 nM, respectively, no inhibition of JNK3, JNK2, and ERK Mus musculus
1-(2,6-dichloro-phenyl)-6-(2,4-difluoro-phenylsulfanyl)-7-(1,2,3,6-tetrahydro-pyridin-4-yl)-3,4-dihydro-1H-pyrido[3,2-d]pyrimidin-2-one highly selective for p38 isozyme alpha wild-type with IC50 of 4.3 nM, the IC50 for mutants G110A and G110D are 61 nM and 160 nM, respectively, no inhibition of JNK3, JNK2, and ERK Mus musculus
BIRB796 binding structure with isozyme p38alpha Mus musculus
additional information structural basis for inhibitor selectivity for p38 over other MAPKs such as ERK or JNK, overview Mus musculus
pyridinyl imidazole-type inhibitors IC50 of 15-48 nM Mus musculus
SB203580 inhibits the p38 isozymes isozymes alpha, beta, and gamma Mus musculus
VK19911
-
Mus musculus
VX745
-
Mus musculus
[4-[3-methyl-2-piperidin-4-yl-5-(3-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-yl]-((S)-1-phenyl-ethyl)-amine highly selective for p38 isozyme alpha wild-type and mutants with IC50 of 0.10-0.14 nM, IC50 for JNK2 is 680 nM, for JNK3 970 nM and for ERK 660 nM Mus musculus

KM Value [mM]

KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
0.048
-
ATP pH 7.0, 30°C, mutant G110D of p38 isozyme alpha Mus musculus
0.085
-
ATP pH 7.0, 30°C, mutant G110A of p38 isozyme alpha Mus musculus
0.096
-
ATP pH 7.0, 30°C, wild-type p38 isozyme alpha Mus musculus

Metals/Ions

Metals/Ions Comment Organism Structure
Mg2+
-
Mus musculus

Organism

Organism UniProt Comment Textmining
Mus musculus P47811 isozymes alpha, beta, gamma, and delta of p38
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
ATP + protein ATF2
-
Mus musculus ADP + phosphorylated protein ATF2
-
?

Synonyms

Synonyms Comment Organism
ERK
-
Mus musculus
JNK2
-
Mus musculus
JNK3
-
Mus musculus
p38alpha MAP kinase
-
Mus musculus

Temperature Optimum [°C]

Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
30
-
assay at Mus musculus

pH Optimum

pH Optimum Minimum pH Optimum Maximum Comment Organism
7
-
assay at Mus musculus

Cofactor

Cofactor Comment Organism Structure
ATP
-
Mus musculus

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.0000001 0.00000014 highly selective for p38 isozyme alpha wild-type and mutants with IC50 of 0.10-0.14 nM Mus musculus [4-[3-methyl-2-piperidin-4-yl-5-(3-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-yl]-((S)-1-phenyl-ethyl)-amine
0.0000043
-
highly selective for p38 isozyme alpha wild-type with IC50 of 4.3 nM, respectively, no inhibition of JNK3, JNK2, and ERK Mus musculus 1-(2,6-dichloro-phenyl)-6-(2,4-difluoro-phenylsulfanyl)-7-(1,2,3,6-tetrahydro-pyridin-4-yl)-3,4-dihydro-1H-pyrido[3,2-d]pyrimidin-2-one
0.000015 0.000048 IC50 of 15-48 nM Mus musculus pyridinyl imidazole-type inhibitors
0.000061
-
IC50 for mutant G110A 61 nM Mus musculus 1-(2,6-dichloro-phenyl)-6-(2,4-difluoro-phenylsulfanyl)-7-(1,2,3,6-tetrahydro-pyridin-4-yl)-3,4-dihydro-1H-pyrido[3,2-d]pyrimidin-2-one
0.00016
-
IC50 mutant G110D 160 nM, respectively, no inhibition of JNK3, JNK2, and ERK Mus musculus 1-(2,6-dichloro-phenyl)-6-(2,4-difluoro-phenylsulfanyl)-7-(1,2,3,6-tetrahydro-pyridin-4-yl)-3,4-dihydro-1H-pyrido[3,2-d]pyrimidin-2-one
0.00066
-
Ic50 for ERK 660 nM Mus musculus [4-[3-methyl-2-piperidin-4-yl-5-(3-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-yl]-((S)-1-phenyl-ethyl)-amine
0.00068
-
IC50 for JNK2 is 680 nM Mus musculus [4-[3-methyl-2-piperidin-4-yl-5-(3-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-yl]-((S)-1-phenyl-ethyl)-amine
0.00097
-
IC50 for JNK3 970 nM Mus musculus [4-[3-methyl-2-piperidin-4-yl-5-(3-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-yl]-((S)-1-phenyl-ethyl)-amine