PDBsum entry 3iw7

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protein ligands links
Transferase PDB id
Protein chain
335 a.a. *
BOG ×3
Waters ×112
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Human p38 map kinase in complex with an imidazo-pyridine
Structure: Mitogen-activated protein kinase 14. Chain: a. Synonym: p38 map kinase, 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: 469008.
2.40Å     R-factor:   0.203     R-free:   0.282
Authors: C.Gruetter,J.R.Simard,D.Rauh
Key ref: J.R.Simard et al. (2009). High-throughput screening to identify inhibitors which stabilize inactive kinase conformations in p38alpha. J Am Chem Soc, 131, 18478-18488. PubMed id: 19950957 DOI: 10.1021/ja907795q
02-Sep-09     Release date:   17-Nov-09    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
Q16539  (MK14_HUMAN) -  Mitogen-activated protein kinase 14
360 a.a.
335 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 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/ja907795q J Am Chem Soc 131:18478-18488 (2009)
PubMed id: 19950957  
High-throughput screening to identify inhibitors which stabilize inactive kinase conformations in p38alpha.
J.R.Simard, C.Grütter, V.Pawar, B.Aust, A.Wolf, M.Rabiller, S.Wulfert, A.Robubi, S.Klüter, C.Ottmann, D.Rauh.
Small molecule kinase inhibitors are an attractive means to modulate kinase activities in medicinal chemistry and chemical biology research. In the physiological setting of a cell, kinase function is orchestrated by a plethora of regulatory processes involving the structural transition of kinases between inactive and enzymatically competent conformations and vice versa. The development of novel kinase inhibitors is mainly fostered by high-throughput screening initiatives where the small molecule perturbation of the phosphorylation reaction is measured to identify inhibitors. Such setups require enzymatically active kinase preparations and present a risk of solely identifying classical ATP-competitive Type I inhibitors. Here we report the high-throughput screening of a library of approximately 35000 small organic molecules with an assay system that utilizes enzymatically inactive human p38alpha MAP kinase to detect stabilizers of the pharmacologically more desirable DFG-out conformation. We used protein X-ray crystallography to characterize the binding mode of hit compounds and reveal structural features which explain how these ligands stabilize and/or induce the DFG-out conformation. Lastly, we show that although some of the hit compounds were confirmed by protein X-ray crystallography, they were not detected in classic phosphorylation assays, thus validating the unique sensitivity of the assay system used in this study and highlighting the potential of screening with inactive kinase preparations.

Literature references that cite this PDB file's key reference

  PubMed id Reference
21095574 L.M.Wodicka, P.Ciceri, M.I.Davis, J.P.Hunt, M.Floyd, S.Salerno, X.H.Hua, J.M.Ford, R.C.Armstrong, P.P.Zarrinkar, and D.K.Treiber (2010).
Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry.
  Chem Biol, 17, 1241-1249.  
20336692 M.Rabiller, M.Getlik, S.Klüter, A.Richters, S.Tückmantel, J.R.Simard, and D.Rauh (2010).
Proteus in the world of proteins: conformational changes in protein kinases.
  Arch Pharm (Weinheim), 343, 193-206.  
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