PDBsum entry 3ds6

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Transferase PDB id
Protein chain
343 a.a. *
A17 ×4
* Residue conservation analysis
PDB id:
Name: Transferase
Title: P38 complex with a phthalazine inhibitor
Structure: 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
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: mapk14, csbp, csbp1, csbp2, cspb1, mxi2. Expressed in: escherichia coli. Expression_system_taxid: 562
2.90Å     R-factor:   0.228     R-free:   0.319
Authors: B.Herberich,R.Syed,V.Li,D.Grosfeld
Key ref: 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: 18817365 DOI: 10.1021/jm8005417
11-Jul-08     Release date:   07-Oct-08    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
Q16539  (MK14_HUMAN) -  Mitogen-activated protein kinase 14
360 a.a.
343 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - Mitogen-activated protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
+ protein
+ phosphoprotein
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cell   8 terms 
  Biological process     intracellular signal transduction   71 terms 
  Biochemical function     nucleotide binding     11 terms  


DOI no: 10.1021/jm8005417 J Med Chem 51:6271-6279 (2008)
PubMed id: 18817365  
Discovery of highly selective and potent p38 inhibitors based on a phthalazine scaffold.
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.
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.

Literature references that cite this PDB file's key reference

  PubMed id Reference
21515047 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.
  Bioorg Med Chem Lett, 21, 3452-3456.  
19876042 L.K.Chico, L.J.Van Eldik, and D.M.Watterson (2009).
Targeting protein kinases in central nervous system disorders.
  Nat Rev Drug Discov, 8, 892-909.  
19665431 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.
  Trends Mol Med, 15, 369-379.  
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