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PDBsum entry 5omh
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PDB id:
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Transferase
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Title:
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P38alpha in complex with pyrazolobenzothiazine inhibitor coxh11
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Structure:
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Mitogen-activated protein kinase 14. Chain: a. Synonym: mapk 14,cytokine suppressive anti-inflammatory drug-binding protein,csbp,map kinase mxi2,max-interacting protein 2,mitogen- activated protein kinase p38 alpha,map kinase p38 alpha,stress- activated protein kinase 2a,sapk2a. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: mapk14, csbp, csbp1, csbp2, cspb1, mxi2, sapk2a. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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2.50Å
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R-factor:
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0.218
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R-free:
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0.277
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Authors:
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M.Buehrmann,D.Rauh
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Key ref:
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D.Bartolini
et al.
(2019).
Co-crystal structure determination and cellular evaluation of 1,4-dihydropyrazolo[4,3-c] [1,2] benzothiazine 5,5-dioxide p38α MAPK inhibitors.
Biochem Biophys Res Commun,
511,
579-586.
PubMed id:
DOI:
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Date:
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31-Jul-17
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Release date:
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13-Mar-19
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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.
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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DOI no:
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Biochem Biophys Res Commun
511:579-586
(2019)
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PubMed id:
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Co-crystal structure determination and cellular evaluation of 1,4-dihydropyrazolo[4,3-c] [1,2] benzothiazine 5,5-dioxide p38α MAPK inhibitors.
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D.Bartolini,
M.Bührmann,
M.L.Barreca,
G.Manfroni,
V.Cecchetti,
D.Rauh,
F.Galli.
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ABSTRACT
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p38α mitogen-activated protein kinase (MAPK) is an attracting pharmacological
target in inflammatory diseases and cancer. Searching for new and more efficient
p38-MAPK inhibitors, two recently developed pyrazolobenzothiazine-based
(COXP4M12 and COXH11) compounds were investigated in this study using a cellular
model of p38 activation. This consisted of HT29 human colorectal adenocarcinoma
cells exposed to H2O2 or lipopolysaccharide (LPS).
Immunoblot data confirmed the inhibitory effect of COXP4M12 and COXH11 on p38
substrate phosphorylation (MAPK-APK2 and ATF2 transcription factor). Compound
cytotoxicity was very low and apparent efficacy of these inhibitors was
comparable with that of SB203580, a commercially available type I inhibitor of
p38. All these compounds also inhibit upstream kinases that promote p38-MAPK
phosphorylation and co-activate the stress-activated protein kinase JNK, while
ERK1/2 MAPK phosphorylation was unaffected. Compound-target kinase interaction
was investigated by means of co-crystallization experiments that provided
further structural and molecular insight on the inhibitory mechanism and
optimization strategy of this new class of p38-MAPK inhibitors.
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Links
