PDBsum entry 2gfs

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Signaling protein, transferase PDB id
Protein chain
344 a.a. *
Waters ×293
* Residue conservation analysis
PDB id:
Name: Signaling protein, transferase
Title: P38 kinase crystal structure in complex with ro3201195
Structure: Mitogen-activated protein kinase 14. Chain: a. 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
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: mapk14, csbp, csbp1, csbp2, mxi2. Expressed in: escherichia coli. Expression_system_taxid: 562
1.75Å     R-factor:   0.205     R-free:   0.239
Authors: S.F.Harris,J.Bertrand,A.Villasenor
Key ref: D.M.Goldstein et al. (2006). Discovery of S-[5-amino-1-(4-fluorophenyl)-1H-pyrazol-4-yl]-[3-(2,3-dihydroxypropoxy)phenyl]methanone (RO3201195), an orally bioavailable and highly selective inhibitor of p38 MAP kinase. J Med Chem, 49, 1562-1575. PubMed id: 16509574 DOI: 10.1021/jm050736c
23-Mar-06     Release date:   18-Apr-06    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
Q16539  (MK14_HUMAN) -  Mitogen-activated protein kinase 14
360 a.a.
344 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/jm050736c J Med Chem 49:1562-1575 (2006)
PubMed id: 16509574  
Discovery of S-[5-amino-1-(4-fluorophenyl)-1H-pyrazol-4-yl]-[3-(2,3-dihydroxypropoxy)phenyl]methanone (RO3201195), an orally bioavailable and highly selective inhibitor of p38 MAP kinase.
D.M.Goldstein, T.Alfredson, J.Bertrand, M.F.Browner, K.Clifford, S.A.Dalrymple, J.Dunn, J.Freire-Moar, S.Harris, S.S.Labadie, J.La Fargue, J.M.Lapierre, S.Larrabee, F.Li, E.Papp, D.McWeeney, C.Ramesha, R.Roberts, D.Rotstein, B.San Pablo, E.B.Sjogren, O.Y.So, F.X.Talamas, W.Tao, A.Trejo, A.Villasenor, M.Welch, T.Welch, P.Weller, P.E.Whiteley, K.Young, S.Zipfel.
A novel class of highly selective inhibitors of p38 MAP kinase was discovered from high throughput screening. The synthesis and optimization of a series of 5-amino-N-phenyl-1H-pyrazol-4-yl-3-phenylmethanones is described. An X-ray crystal structure of this series bound in the ATP binding pocket of unphosphorylated p38alpha established the presence of a unique hydrogen bond between the exocyclic amine of the inhibitor and threonine 106 which likely contributes to the selectivity for p38. The crystallographic information was used to optimize the potency and physicochemical properties of the series. The incorporation of the 2,3-dihydroxypropoxy moiety on the pyrazole scaffold resulted in a compound with excellent drug-like properties including high oral bioavailability. These efforts identified 63 (RO3201195) as an orally bioavailable and highly selective inhibitor of p38 which was selected for advancement into Phase I clinical trials.

Literature references that cite this PDB file's key reference

  PubMed id Reference
21280133 A.Kuglstatter, A.Wong, S.Tsing, S.W.Lee, Y.Lou, A.G.Villaseñor, J.M.Bradshaw, D.Shaw, J.W.Barnett, and M.F.Browner (2011).
Insights into the conformational flexibility of Bruton's tyrosine kinase from multiple ligand complex structures.
  Protein Sci, 20, 428-436.
PDB codes: 3pix 3piy 3piz 3pj1 3pj2 3pj3
20810542 A.J.Olaharski, H.Bitter, N.Gonzaludo, R.Kondru, D.M.Goldstein, T.S.Zabka, H.Lin, T.Singer, and K.Kolaja (2010).
Modeling bone marrow toxicity using kinase structural motifs and the inhibition profiles of small molecular kinase inhibitors.
  Toxicol Sci, 118, 266-275.  
20160879 R.S.Armen, J.Chen, and C.L.Brooks (2009).
An Evaluation of Explicit Receptor Flexibility in Molecular Docking Using Molecular Dynamics and Torsion Angle Molecular Dynamics.
  J Chem Theory Comput, 5, 2909-2923.  
19261605 T.Kamenecka, J.Habel, D.Duckett, W.Chen, Y.Y.Ling, B.Frackowiak, R.Jiang, Y.Shin, X.Song, and P.Lograsso (2009).
Structure-Activity Relationships and X-ray Structures Describing the Selectivity of Aminopyrazole Inhibitors for c-Jun N-terminal Kinase 3 (JNK3) over p38.
  J Biol Chem, 284, 12853-12861.
PDB codes: 3fi2 3fi3
17827184 G.Schett, J.Zwerina, and G.Firestein (2008).
The p38 mitogen-activated protein kinase (MAPK) pathway in rheumatoid arthritis.
  Ann Rheum Dis, 67, 909-916.  
18685771 V.Chudasama, and J.D.Wilden (2008).
A versatile synthesis of 2,4-substituted oxazoles.
  Chem Commun (Camb), (), 3768-3770.  
18989991 Y.A.Ivanenkov, K.V.Balakin, and S.E.Tkachenko (2008).
New approaches to the treatment of inflammatory disease : focus on small-molecule inhibitors of signal transduction pathways.
  Drugs R D, 9, 397-434.  
17390370 O.McConnell, A.Bach, C.Balibar, N.Byrne, Y.Cai, G.Carter, M.Chlenov, L.Di, K.Fan, I.Goljer, Y.He, D.Herold, M.Kagan, E.Kerns, F.Koehn, C.Kraml, V.Marathias, B.Marquez, L.McDonald, L.Nogle, C.Petucci, G.Schlingmann, G.Tawa, M.Tischler, R.T.Williamson, A.Sutherland, W.Watts, M.Young, M.Y.Zhang, Y.Zhang, D.Zhou, and D.Ho (2007).
Enantiomeric separation and determination of absolute stereochemistry of asymmetric molecules in drug discovery: building chiral technology toolboxes.
  Chirality, 19, 658-682.  
17541990 S.Margutti, and S.A.Laufer (2007).
Are MAP Kinases Drug Targets? Yes, but Difficult Ones.
  ChemMedChem, 2, 1116-1140.  
17460211 T.Davis, F.S.Wyllie, M.J.Rokicki, M.C.Bagley, and D.Kipling (2007).
The role of cellular senescence in Werner syndrome: toward therapeutic intervention in human premature aging.
  Ann N Y Acad Sci, 1100, 455-469.  
17009360 O.Prien (2006).
The gatekeeper: friend or foe in identifying the next generation of kinase inhibitors.
  ChemMedChem, 1, 1195-1196.  
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. Where a reference describes a PDB structure, the PDB codes are shown on the right.