PDBsum entry 1p38

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protein links
Transferase PDB id
Protein chain
351 a.a. *
Waters ×129
* Residue conservation analysis
PDB id:
Name: Transferase
Title: The structure of the map kinase p38 at 2.1 angstoms resolution
Structure: Map kinase p38. Chain: a. Synonym: mitogen activated protein kinase. Engineered: yes. Mutation: yes
Source: Mus musculus. House mouse. Organism_taxid: 10090. Cell_line: bl21. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
2.10Å     R-factor:   0.212     R-free:   0.244
Authors: Z.Wang,P.C.Harkins,R.J.Ulevitch,J.Han,M.H.Cobb,E.J.Goldsmith
Key ref:
Z.Wang et al. (1997). The structure of mitogen-activated protein kinase p38 at 2.1-A resolution. Proc Natl Acad Sci U S A, 94, 2327-2332. PubMed id: 9122194 DOI: 10.1073/pnas.94.6.2327
06-Jan-97     Release date:   21-Jan-98    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P47811  (MK14_MOUSE) -  Mitogen-activated protein kinase 14
360 a.a.
351 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   7 terms 
  Biological process     intracellular signal transduction   40 terms 
  Biochemical function     nucleotide binding     10 terms  


DOI no: 10.1073/pnas.94.6.2327 Proc Natl Acad Sci U S A 94:2327-2332 (1997)
PubMed id: 9122194  
The structure of mitogen-activated protein kinase p38 at 2.1-A resolution.
Z.Wang, P.C.Harkins, R.J.Ulevitch, J.Han, M.H.Cobb, E.J.Goldsmith.
The structure of mitogen-activated protein (MAP) kinase p38 has been solved at 2.1-A to an R factor of 21.0%, making p38 the second low activity MAP kinase solved to date. Although p38 is topologically similar to the MAP kinase ERK2, the phosphorylation Lip (a regulatory loop near the active site) adopts a different fold in p38. The peptide substrate binding site and the ATP binding site are also different from those of ERK2. The results explain why MAP kinases are specific for different activating enzymes, substrates, and inhibitors. A model presented for substrate and activator interactions has implications for the evolution of protein kinase cascades.
  Selected figure(s)  
Figure 1.
Fig. 1. Electron density, around the phosphorylation sites Thr-180 and Tyr-182 and around the P+1 specificity pocket, contoured at 1.25 and drawn in O (31). The map was calculated with the program REFMAC in CCP4 (33) with sigmaA weighted coefficients (32) and model-derived phases. Dashed yellow lines denote hydrogen bonds between Arg-186 and the backbone carbonyls of Met-179 and^ Gly-181. The dashed red line denotes stacking interaction between Gly-181 and the backbone carbonyl of Thr-226 (distance of 3.1^ Å).
Figure 4.
Fig. 4. The P+1 specificity pocket and phosphorylation Lip region of p38 (a) and ERK2 (b) drawn in SETOR. In p38, the shorter Lip is formed into a helical turn near the P+1 site, and the phosphorylation site tyrosine is on the surface. In ERK2, the Lip takes a wide^ excursion around the side chains of a neighboring surface loop, and the phosphorylation site tyrosine is buried. p38 superimposed^ on ERK2 in the neighborhood of the ATP binding site identified^ in ERK2 (c) and putative substrate binding site (d). Dark gray denotes p38; light gray and italic labeling denote ERK2.
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21134636 R.Akella, X.Min, Q.Wu, K.H.Gardner, and E.J.Goldsmith (2010).
The third conformation of p38α MAP kinase observed in phosphorylated p38α and in solution.
  Structure, 18, 1571-1578.
PDB code: 3p4k
19706521 A.Bakan, and I.Bahar (2009).
The intrinsic dynamics of enzymes plays a dominant role in determining the structural changes induced upon inhibitor binding.
  Proc Natl Acad Sci U S A, 106, 14349-14354.  
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
18704950 K.O.Wrzeszczynski, and B.Rost (2009).
Cell cycle kinases predicted from conserved biophysical properties.
  Proteins, 74, 655-668.  
19011223 L.Jirmanova, D.N.Sarma, D.Jankovic, P.R.Mittelstadt, and J.D.Ashwell (2009).
Genetic disruption of p38alpha Tyr323 phosphorylation prevents T-cell receptor-mediated p38alpha activation and impairs interferon-gamma production.
  Blood, 113, 2229-2237.  
18941902 R.Gil-Redondo, J.Estrada, A.Morreale, F.Herranz, J.Sancho, and A.R.Ortiz (2009).
VSDMIP: virtual screening data management on an integrated platform.
  J Comput Aided Mol Des, 23, 171-184.  
19651772 R.Scholz, M.Suter, T.Weimann, C.Polge, P.V.Konarev, R.F.Thali, R.D.Tuerk, B.Viollet, T.Wallimann, U.Schlattner, and D.Neumann (2009).
Homo-oligomerization and activation of AMP-activated protein kinase are mediated by the kinase domain alphaG-helix.
  J Biol Chem, 284, 27425-27437.  
19141286 X.Min, R.Akella, H.He, J.M.Humphreys, S.E.Tsutakawa, S.J.Lee, J.A.Tainer, M.H.Cobb, and E.J.Goldsmith (2009).
The structure of the MAP2K MEK6 reveals an autoinhibitory dimer.
  Structure, 17, 96.
PDB code: 3enm
18566506 J.S.Sack, K.F.Kish, M.Pokross, D.Xie, G.J.Duke, J.A.Tredup, S.E.Kiefer, and J.A.Newitt (2008).
Structural basis for the high-affinity binding of pyrrolotriazine inhibitors of p38 MAP kinase.
  Acta Crystallogr D Biol Crystallogr, 64, 705-710.  
18501927 K.M.Sours, S.C.Kwok, T.Rachidi, T.Lee, A.Ring, A.N.Hoofnagle, K.A.Resing, and N.G.Ahn (2008).
Hydrogen-exchange mass spectrometry reveals activation-induced changes in the conformational mobility of p38alpha MAP kinase.
  J Mol Biol, 379, 1075-1093.  
18068683 R.Akella, T.M.Moon, and E.J.Goldsmith (2008).
Unique MAP Kinase binding sites.
  Biochim Biophys Acta, 1784, 48-55.  
17395714 A.White, C.A.Pargellis, J.M.Studts, B.G.Werneburg, and B.T.Farmer (2007).
Molecular basis of MAPK-activated protein kinase 2:p38 assembly.
  Proc Natl Acad Sci U S A, 104, 6353-6358.
PDB code: 2oza
17694525 D.Kuhn, N.Weskamp, E.Hüllermeier, and G.Klebe (2007).
Functional Classification of Protein Kinase Binding Sites Using Cavbase.
  ChemMedChem, 2, 1432-1447.  
17241234 M.Avitzour, R.Diskin, B.Raboy, N.Askari, D.Engelberg, and O.Livnah (2007).
Intrinsically active variants of all human p38 isoforms.
  FEBS J, 274, 963-975.  
17349032 M.Lenassi, T.Vaupotic, N.Gunde-Cimerman, and A.Plemenitas (2007).
The MAP kinase HwHog1 from the halophilic black yeast Hortaea werneckii: coping with stresses in solar salterns.
  Saline Systems, 3, 3.  
17496909 M.Raman, W.Chen, and M.H.Cobb (2007).
Differential regulation and properties of MAPKs.
  Oncogene, 26, 3100-3112.  
17466055 R.Chen-Chih Wu, M.F.Shaio, and W.L.Cho (2007).
A p38 MAP kinase regulates the expression of the Aedes aegypti defensin gene in mosquito cells.
  Insect Mol Biol, 16, 389-399.  
17242519 R.Diskin, D.Engelberg, and O.Livnah (2007).
High-resolution diffracting crystals of intrinsically active p38alpha MAP kinase: a case study for low-throughput approaches.
  Acta Crystallogr D Biol Crystallogr, 63, 260-265.  
17541990 S.Margutti, and S.A.Laufer (2007).
Are MAP Kinases Drug Targets? Yes, but Difficult Ones.
  ChemMedChem, 2, 1116-1140.  
16374788 M.Vogtherr, K.Saxena, S.Hoelder, S.Grimme, M.Betz, U.Schieborr, B.Pescatore, M.Robin, L.Delarbre, T.Langer, K.U.Wendt, and H.Schwalbe (2006).
NMR characterization of kinase p38 dynamics in free and ligand-bound forms.
  Angew Chem Int Ed Engl, 45, 993-997.
PDB code: 2ewa
16156785 A.E.Szafranska, and K.N.Dalby (2005).
Kinetic mechanism for p38 MAP kinase alpha. A partial rapid-equilibrium random-order ternary-complex mechanism for the phosphorylation of a protein substrate.
  FEBS J, 272, 4631-4645.  
16084385 A.Kohl, P.Amstutz, P.Parizek, H.K.Binz, C.Briand, G.Capitani, P.Forrer, A.Plückthun, and M.G.Grütter (2005).
Allosteric inhibition of aminoglycoside phosphotransferase by a designed ankyrin repeat protein.
  Structure, 13, 1131-1141.
PDB code: 2bkk
15316926 G.Pelaia, G.Cuda, A.Vatrella, L.Gallelli, M.Caraglia, M.Marra, A.Abbruzzese, M.Caputi, R.Maselli, F.S.Costanzo, and S.A.Marsico (2005).
Mitogen-activated protein kinases and asthma.
  J Cell Physiol, 202, 642-653.  
16013076 U.Schieborr, M.Vogtherr, B.Elshorst, M.Betz, S.Grimme, B.Pescatore, T.Langer, K.Saxena, and H.Schwalbe (2005).
How much NMR data is required to determine a protein-ligand complex structure?
  Chembiochem, 6, 1891-1898.  
15036210 C.Jones, and K.Moses (2004).
Cell-cycle regulation and cell-type specification in the developing Drosophila compound eye.
  Semin Cell Dev Biol, 15, 75-81.  
15343278 N.J.Dibb, S.M.Dilworth, and C.D.Mol (2004).
Switching on kinases: oncogenic activation of BRAF and the PDGFR family.
  Nat Rev Cancer, 4, 718-727.  
15273306 N.Kannan, and A.F.Neuwald (2004).
Evolutionary constraints associated with functional specificity of the CMGC protein kinases MAPK, CDK, GSK, SRPK, DYRK, and CK2alpha.
  Protein Sci, 13, 2059-2077.  
15187187 P.P.Roux, and J.Blenis (2004).
ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions.
  Microbiol Mol Biol Rev, 68, 320-344.  
12832470 G.Yaakov, M.Bell, S.Hohmann, and D.Engelberg (2003).
Combination of two activating mutations in one HOG1 gene forms hyperactive enzymes that induce growth arrest.
  Mol Cell Biol, 23, 4826-4840.  
12835387 J.P.Kumar, F.Hsiung, M.A.Powers, and K.Moses (2003).
Nuclear translocation of activated MAP kinase is developmentally regulated in the developing Drosophila eye.
  Development, 130, 3703-3714.  
12951578 S.Kumar, J.Boehm, and J.C.Lee (2003).
p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases.
  Nat Rev Drug Discov, 2, 717-726.  
12086621 C.I.Chang, B.E.Xu, R.Akella, M.H.Cobb, and E.J.Goldsmith (2002).
Crystal structures of MAP kinase p38 complexed to the docking sites on its nuclear substrate MEF2A and activator MKK3b.
  Mol Cell, 9, 1241-1249.
PDB codes: 1lew 1lez
11804650 J.M.English, and M.H.Cobb (2002).
Pharmacological inhibitors of MAPK pathways.
  Trends Pharmacol Sci, 23, 40-45.  
12191611 T.Tanoue, and E.Nishida (2002).
Docking interactions in the mitogen-activated protein kinase cascades.
  Pharmacol Ther, 93, 193-202.  
11592393 K.Zwerger, and H.Hirt (2001).
Recent advances in plant MAP kinase signalling.
  Biol Chem, 382, 1123-1131.  
11440715 R.Dajani, E.Fraser, S.M.Roe, N.Young, V.Good, T.C.Dale, and L.H.Pearl (2001).
Crystal structure of glycogen synthase kinase 3 beta: structural basis for phosphate-primed substrate specificity and autoinhibition.
  Cell, 105, 721-732.
PDB code: 1h8f
11157753 T.Tanoue, R.Maeda, M.Adachi, and E.Nishida (2001).
Identification of a docking groove on ERK and p38 MAP kinases that regulates the specificity of docking interactions.
  EMBO J, 20, 466-479.  
10889467 D.Fox, and A.G.Smulian (2000).
Mkp1 of Pneumocystis carinii associates with the yeast transcription factor Rlm1 via a mechanism independent of the activation state.
  Cell Signal, 12, 381-390.  
  10794408 D.R.Caffrey, L.A.O'Neill, and D.C.Shields (2000).
A method to predict residues conferring functional differences between related proteins: application to MAP kinase pathways.
  Protein Sci, 9, 655-670.  
10878576 E.Martín-Blanco (2000).
p38 MAPK signalling cascades: ancient roles and new functions.
  Bioessays, 22, 637-645.  
10684658 G.Chen, M.D.Porter, J.R.Bristol, M.J.Fitzgibbon, and S.Pazhanisamy (2000).
Kinetic mechanism of the p38-alpha MAP kinase: phosphoryl transfer to synthetic peptides.
  Biochemistry, 39, 2079-2087.  
10878289 J.C.Lee, S.Kumar, D.E.Griswold, D.C.Underwood, B.J.Votta, and J.L.Adams (2000).
Inhibition of p38 MAP kinase as a therapeutic strategy.
  Immunopharmacology, 47, 185-201.  
10676842 K.Ono, and J.Han (2000).
The p38 signal transduction pathway: activation and function.
  Cell Signal, 12, 1.  
10807318 T.Obata, G.E.Brown, and M.B.Yaffe (2000).
MAP kinase pathways activated by stress: the p38 MAPK pathway.
  Crit Care Med, 28, N67-N77.  
10655591 T.Tanoue, M.Adachi, T.Moriguchi, and E.Nishida (2000).
A conserved docking motif in MAP kinases common to substrates, activators and regulators.
  Nat Cell Biol, 2, 110-116.  
10454214 J.C.Lee, S.Kassis, S.Kumar, A.Badger, and J.L.Adams (1999).
p38 mitogen-activated protein kinase inhibitors--mechanisms and therapeutic potentials.
  Pharmacol Ther, 82, 389-397.  
10454194 J.M.Sowadski, L.F.Epstein, L.Lankiewicz, and R.Karlsson (1999).
Conformational diversity of catalytic cores of protein kinases.
  Pharmacol Ther, 82, 157-164.  
10025408 M.Huse, Y.G.Chen, J.Massagué, and J.Kuriyan (1999).
Crystal structure of the cytoplasmic domain of the type I TGF beta receptor in complex with FKBP12.
  Cell, 96, 425-436.
PDB code: 1b6c
10454215 Y.Fukami, A.A.Tokmakov, K.Konaka, and K.Sato (1999).
Peptide inhibitors of the mitogen-activated protein kinase pathway: a structure -mimetic peptide corresponding to the conserved inter-DFG-APE region in the kinase domain.
  Pharmacol Ther, 82, 399-407.  
9604935 A.V.Khokhlatchev, B.Canagarajah, J.Wilsbacher, M.Robinson, M.Atkinson, E.Goldsmith, and M.H.Cobb (1998).
Phosphorylation of the MAP kinase ERK2 promotes its homodimerization and nuclear translocation.
  Cell, 93, 605-615.  
9753474 B.Frantz, T.Klatt, M.Pang, J.Parsons, A.Rolando, H.Williams, M.J.Tocci, S.J.O'Keefe, and E.A.O'Neill (1998).
The activation state of p38 mitogen-activated protein kinase determines the efficiency of ATP competition for pyridinylimidazole inhibitor binding.
  Biochemistry, 37, 13846-13853.  
  9618441 F.Banuett (1998).
Signalling in the yeasts: an informational cascade with links to the filamentous fungi.
  Microbiol Mol Biol Rev, 62, 249-274.  
  9585506 F.Gaits, G.Degols, K.Shiozaki, and P.Russell (1998).
Phosphorylation and association with the transcription factor Atf1 regulate localization of Spc1/Sty1 stress-activated kinase in fission yeast.
  Genes Dev, 12, 1464-1473.  
9564044 M.Wiese (1998).
A mitogen-activated protein (MAP) kinase homologue of Leishmania mexicana is essential for parasite survival in the infected host.
  EMBO J, 17, 2619-2628.  
  9827991 T.Fox, J.T.Coll, X.Xie, P.J.Ford, U.A.Germann, M.D.Porter, S.Pazhanisamy, M.A.Fleming, V.Galullo, M.S.Su, and K.P.Wilson (1998).
A single amino acid substitution makes ERK2 susceptible to pyridinyl imidazole inhibitors of p38 MAP kinase.
  Protein Sci, 7, 2249-2255.
PDB code: 1pme
9760235 X.Cheng, S.Shaltiel, and S.S.Taylor (1998).
Mapping substrate-induced conformational changes in cAMP-dependent protein kinase by protein footprinting.
  Biochemistry, 37, 14005-14013.  
9753691 Z.Wang, B.J.Canagarajah, J.C.Boehm, S.Kassisà, M.H.Cobb, P.R.Young, S.Abdel-Meguid, J.L.Adams, and E.J.Goldsmith (1998).
Structural basis of inhibitor selectivity in MAP kinases.
  Structure, 6, 1117-1128.
PDB codes: 1a9u 1bl6 1bl7 1bmk 3erk 4erk
9492189 K.Hardy, and G.Chaudhri (1997).
Activation and signal transduction via mitogen-activated protein (MAP) kinases in T lymphocytes.
  Immunol Cell Biol, 75, 528-545.  
9667861 S.S.Taylor, and E.Radzio-Andzelm (1997).
Protein kinase inhibition: natural and synthetic variations on a theme.
  Curr Opin Chem Biol, 1, 219-226.  
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.