PDBsum entry 2npq

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Transferase PDB id
Protein chain
326 a.a. *
BOG ×2
Waters ×331
* Residue conservation analysis
PDB id:
Name: Transferase
Title: A novel lipid binding site in the p38 alpha map kinase
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. Expressed in: escherichia coli. Expression_system_taxid: 562.
1.80Å     R-factor:   0.205     R-free:   0.245
Authors: R.Diskin,D.Engelberg,O.Livnah
Key ref:
R.Diskin et al. (2008). A novel lipid binding site formed by the MAP kinase insert in p38 alpha. J Mol Biol, 375, 70-79. PubMed id: 17999933 DOI: 10.1016/j.jmb.2007.09.002
29-Oct-06     Release date:   16-Oct-07    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
Q16539  (MK14_HUMAN) -  Mitogen-activated protein kinase 14
360 a.a.
326 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: 10.1016/j.jmb.2007.09.002 J Mol Biol 375:70-79 (2008)
PubMed id: 17999933  
A novel lipid binding site formed by the MAP kinase insert in p38 alpha.
R.Diskin, D.Engelberg, O.Livnah.
The p38 mitogen-activated protein (MAP) kinases function as signaling molecules essential for many cellular processes, particularly mediating stress response. The activity of p38 MAP kinases is meticulously regulated to reach the desired cellular phenotype. Several alternative activation and attenuation mechanisms have been characterized recently which include new phosphorylation sites. Here we present the crystal structure of p38 alpha MAP kinase in complex with n-octyl-beta-glucopyranoside detergent. The complex unveils a novel lipid-binding site formed by a local conformational change of the MAP kinase insert. This binding is the first attribution for a possible role of the MAP kinase insert in p38. The binding site can accommodate a large selection of lipidic molecules. In addition, we also show via biophysical methods that arachidonic acid and its derivatives bind p38 alpha in vitro. Based on our analysis we propose that the binding of lipids could fine-tune p38 alpha catalytic activity towards a preferred phenotype.
  Selected figure(s)  
Figure 1.
Figure 1. Overall structure. (a) Structural alignment of the p38α – β-OG complex (green) and native p38α (gray) using the coordinate of PDB ID 1P38.^19 The phosphorylation lip of the native p38 as well as the N′ and C′ lobes are indicated. The phosphorylation lip of the β-OG complex is not shown due to local disorder. The overall kinase topology is maintained although a minor change in the inter-lobe orientation is apparent. All molecular graphics shown here were rendered using PyMol []. (b) Ribbon representation of the p38α – β-OG complex with the two β-OG molecules shown as spheres. The MAP kinase insert is shown in gray. The β-OG 1 (carbon atoms shown in orange) is characterized by the relatively lower B-factor whereas β-OG 2 (carbon atoms shown in magenta) by higher values (see Table 1). (c) Difference electron density map (F[obs]–F[calc]) calculated at a 2.0σ cutoff at the resolution range of 32.7 Å−1.8 Å after the initial cycle of refinement without β-OG in the model, superimposed with the final coordinates of the p38α – β-OG complex. The map clearly indicates the presence of β-OG in site 1.
Figure 3.
Figure 3. Structural characteristics of β-OG binding to p38α. (a) Superimposition of the p38α – β-OG complex (green) and native p38α (gray) in the vicinity of the MAP kinase insert. The β-OG molecules are represented as spheres in orange and magenta for β-OG 1 and 2, respectively. Trp197 and Met198 from the αEF/αF loop of native p38α and the p38α – β-OG complex are shown as sticks. The MAP kinase insert goes through a conformational change and opens up to accommodate the β-OG molecule. In addition the αEF/αF loop including Trp197 and Met198 goes through a substantial conformational change. In this context, Trp197 forms a hydrophobic interaction with the aliphatic segment of the detergent molecule. (b) Surface representation of p38α displaying the shape of the lipid binding site that accommodates β-OG 1 (orange) and β-OG 2 (magenta). β-OG 1 is extensively buried in the binding site whereas only the lipid tail of β-OG 2 interacts with the protein. The MAP kinase insert is highlighted in a darker surface colour.
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2008, 375, 70-79) copyright 2008.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21256157 R.Eglen, and T.Reisine (2011).
Drug discovery and the human kinome: recent trends.
  Pharmacol Ther, 130, 144-156.  
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.  
20017116 R.L.Rich, and D.G.Myszka (2010).
Grading the commercial optical biosensor literature-Class of 2008: 'The Mighty Binders'.
  J Mol Recognit, 23, 1.  
19501598 J.J.Perry, R.M.Harris, D.Moiani, A.J.Olson, and J.A.Tainer (2009).
p38alpha MAP kinase C-terminal domain binding pocket characterized by crystallographic and computational analyses.
  J Mol Biol, 391, 1.
PDB code: 3hvc
19679652 Y.Choi, M.A.Seeliger, S.B.Panjarian, H.Kim, X.Deng, T.Sim, B.Couch, A.J.Koleske, T.E.Smithgall, and N.S.Gray (2009).
N-myristoylated c-Abl tyrosine kinase localizes to the endoplasmic reticulum upon binding to an allosteric inhibitor.
  J Biol Chem, 284, 29005-29014.  
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 code is shown on the right.