PDBsum entry 2baj

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Transferase PDB id
Jmol PyMol
Protein chain
337 a.a. *
Waters ×106
* Residue conservation analysis
PDB id:
Name: Transferase
Title: P38alpha bound to pyrazolourea
Structure: Mitogen-activated protein kinase 14. Chain: a. Synonym: map kinase p38 alpha. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: mapk14, csbp, csbp1, csbp2, mxi2. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_cell_line: bl21(de3).
2.25Å     R-factor:   0.221     R-free:   0.303
Authors: S.Gerhardt,R.A.Pauptit,J.Read,J.Breed,R.A.Norman,W.H.Ward
Key ref:
J.E.Sullivan et al. (2005). Prevention of MKK6-dependent activation by binding to p38alpha MAP kinase. Biochemistry, 44, 16475-16490. PubMed id: 16342939 DOI: 10.1021/bi051714v
14-Oct-05     Release date:   06-Dec-05    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
Q16539  (MK14_HUMAN) -  Mitogen-activated protein kinase 14
360 a.a.
337 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 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     extracellular region   12 terms 
  Biological process     intracellular signal transduction   65 terms 
  Biochemical function     nucleotide binding     13 terms  


DOI no: 10.1021/bi051714v Biochemistry 44:16475-16490 (2005)
PubMed id: 16342939  
Prevention of MKK6-dependent activation by binding to p38alpha MAP kinase.
J.E.Sullivan, G.A.Holdgate, D.Campbell, D.Timms, S.Gerhardt, J.Breed, A.L.Breeze, A.Bermingham, R.A.Pauptit, R.A.Norman, K.J.Embrey, J.Read, W.S.VanScyoc, W.H.Ward.
Inhibition of p38alpha MAP kinase is a potential approach for the treatment of inflammatory disorders. MKK6-dependent phosphorylation on the activation loop of p38alpha increases its catalytic activity and affinity for ATP. An inhibitor, BIRB796, binds at a site used by the purine moiety of ATP and extends into a "selectivity pocket", which is not used by ATP. It displaces the Asp168-Phe169-Gly170 motif at the start of the activation loop, promoting a "DFG-out" conformation. Some other inhibitors bind only in the purine site, with p38alpha remaining in a "DFG-in" conformation. We now demonstrate that selectivity pocket compounds prevent MKK6-dependent activation of p38alpha in addition to inhibiting catalysis by activated p38alpha. Inhibitors using only the purine site do not prevent MKK6-dependent activation. We present kinetic analyses of seven inhibitors, whose crystal structures as complexes with p38alpha have been determined. This work includes four new crystal structures and a novel assay to measure K(d) for nonactivated p38alpha. Selectivity pocket compounds associate with p38alpha over 30-fold more slowly than purine site compounds, apparently due to low abundance of the DFG-out conformation. At concentrations that inhibit cellular production of an inflammatory cytokine, TNFalpha, selectivity pocket compounds decrease levels of phosphorylated p38alpha and beta. Stabilization of a DFG-out conformation appears to interfere with recognition of p38alpha as a substrate by MKK6. ATP competes less effectively for prevention of activation than for inhibition of catalysis. By binding to a different conformation of the enzyme, compounds that prevent activation offer an alternative approach to modulation of p38alpha.

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.  
20189109 P.Ranjitkar, A.M.Brock, and D.J.Maly (2010).
Affinity reagents that target a specific inactive form of protein kinases.
  Chem Biol, 17, 195-206.  
20071676 Y.Du, J.Tang, G.Li, L.Berti-Mattera, C.A.Lee, D.Bartkowski, D.Gale, J.Monahan, M.R.Niesman, G.Alton, and T.S.Kern (2010).
Effects of p38 MAPK inhibition on early stages of diabetic retinopathy and sensory nerve function.
  Invest Ophthalmol Vis Sci, 51, 2158-2164.  
19152365 F.Fontaine, S.Cross, G.Plasencia, M.Pastor, and I.Zamora (2009).
SHOP: a method for structure-based fragment and scaffold hopping.
  ChemMedChem, 4, 427-439.  
18493651 B.G.Perera, and D.J.Maly (2008).
Design, synthesis and characterization of "clickable" 4-anilinoquinazoline kinase inhibitors.
  Mol Biosyst, 4, 542-550.  
19053777 I.Kufareva, and R.Abagyan (2008).
Type-II kinase inhibitor docking, screening, and profiling using modified structures of active kinase states.
  J Med Chem, 51, 7921-7932.  
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.  
17646926 K.H.Kim (2007).
Outliers in SAR and QSAR: 2. Is a flexible binding site a possible source of outliers?
  J Comput Aided Mol Des, 21, 421-435.  
17312972 M.C.Bagley, T.Davis, M.C.Dix, C.S.Widdowson, and D.Kipling (2006).
Microwave-assisted synthesis of N-pyrazole ureas and the p38alpha inhibitor BIRB 796 for study into accelerated cell ageing.
  Org Biomol Chem, 4, 4158-4164.  
16640460 N.M.Levinson, O.Kuchment, K.Shen, M.A.Young, M.Koldobskiy, M.Karplus, P.A.Cole, and J.Kuriyan (2006).
A Src-like inactive conformation in the abl tyrosine kinase domain.
  PLoS Biol, 4, e144.
PDB codes: 2g1t 2g2f 2g2h 2g2i
17125150 R.L.Rich, and D.G.Myszka (2006).
Survey of the year 2005 commercial optical biosensor literature.
  J Mol Recognit, 19, 478-534.  
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.