PDBsum entry 1pme

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Transferase PDB id
Protein chain
334 a.a. *
Waters ×211
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Structure of penta mutant human erk2 map kinase complexed with a specific inhibitor of human p38 map kinase
Structure: Erk2. Chain: a. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: erk2. Expressed in: escherichia coli. Expression_system_taxid: 562.
2.00Å     R-factor:   0.212     R-free:   0.273
Authors: X.Xie
Key ref:
T.Fox et al. (1998). A single amino acid substitution makes ERK2 susceptible to pyridinyl imidazole inhibitors of p38 MAP kinase. Protein Sci, 7, 2249-2255. PubMed id: 9827991 DOI: 10.1002/pro.5560071102
08-Jun-98     Release date:   08-Jun-99    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P28482  (MK01_HUMAN) -  Mitogen-activated protein kinase 1
360 a.a.
334 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 6 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     protein complex   21 terms 
  Biological process     viral reproduction   74 terms 
  Biochemical function     nucleotide binding     15 terms  


DOI no: 10.1002/pro.5560071102 Protein Sci 7:2249-2255 (1998)
PubMed id: 9827991  
A single amino acid substitution makes ERK2 susceptible to pyridinyl imidazole inhibitors of p38 MAP kinase.
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, K.P.Wilson.
Mitogen-activated protein (MAP) kinases are serine/threonine kinases that mediate intracellular signal transduction pathways. Pyridinyl imidazole compounds block pro-inflammatory cytokine production and are specific p38 kinase inhibitors. ERK2 is related to p38 in sequence and structure, but is not inhibited by pyridinyl imidazole inhibitors. Crystal structures of two pyridinyl imidazoles complexed with p38 revealed these compounds bind in the ATP site. Mutagenesis data suggested a single residue difference at threonine 106 between p38 and other MAP kinases is sufficient to confer selectivity of pyridinyl imidazoles. We have changed the equivalent residue in human ERK2, Q105, into threonine and alanine, and substituted four additional ATP binding site residues. The single residue change Q105A in ERK2 enhances the binding of SB202190 at least 25,000-fold compared to wild-type ERK2. We report enzymatic analyses of wild-type ERK2 and the mutant proteins, and the crystal structure of a pyridinyl imidazole, SB203580, bound to an ERK2 pentamutant, I103L, Q105T, D106H, E109G. T110A. These ATP binding site substitutions induce low nanomolar sensitivity to pyridinyl imidazoles. Furthermore, we identified 5-iodotubercidin as a potent ERK2 inhibitor, which may help reveal the role of ERK2 in cell proliferation.
  Selected figure(s)  
Figure 1.
Fig. 1. A: Chemicalstructures of ERK2 and p38 inhibitors I)
Figure 2.
Fig. 2. See figurecaption n faingpage.
  The above figures are reprinted by permission from the Protein Society: Protein Sci (1998, 7, 2249-2255) copyright 1998.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
  21249167 M.Glover, C.Sweeny, B.Davis, and K.M.O'Shaughnessy (2010).
A Single Amino Acid Substitution Makes WNK4 Susceptible to SB 203580 and SB 202190.
  Open Med Chem J, 4, 57-61.  
19943848 M.L.Moldrup, B.Georg, B.Falktoft, R.Mortensen, J.L.Hansen, and J.Fahrenkrug (2010).
Light induces Fos expression via extracellular signal-regulated kinases 1/2 in melanopsin-expressing PC12 cells.
  J Neurochem, 112, 797-806.  
  19557293 A.Gruzman, G.Babai, and S.Sasson (2009).
Adenosine Monophosphate-Activated Protein Kinase (AMPK) as a New Target for Antidiabetic Drugs: A Review on Metabolic, Pharmacological and Chemical Considerations.
  Rev Diabet Stud, 6, 13-36.  
19032760 D.R.Caffrey, E.A.Lunney, and D.J.Moshinsky (2008).
Prediction of specificity-determining residues for small-molecule kinase inhibitors.
  BMC Bioinformatics, 9, 491.  
18230760 G.Mayer, B.Wulffen, C.Huber, J.Brockmann, B.Flicke, L.Neumann, D.Hafenbradl, B.M.Klebl, M.J.Lohse, C.Krasel, and M.Blind (2008).
An RNA molecule that specifically inhibits G-protein-coupled receptor kinase 2 in vitro.
  RNA, 14, 524-534.  
17694525 D.Kuhn, N.Weskamp, E.Hüllermeier, and G.Klebe (2007).
Functional Classification of Protein Kinase Binding Sites Using Cavbase.
  ChemMedChem, 2, 1432-1447.  
17240048 G.M.Cheetham, P.A.Charlton, J.M.Golec, and J.R.Pollard (2007).
Structural basis for potent inhibition of the Aurora kinases and a T315I multi-drug resistant mutant form of Abl kinase by VX-680.
  Cancer Lett, 251, 323-329.  
17726105 H.Nakanishi, T.Nakamura, E.Canaani, and C.M.Croce (2007).
ALL1 fusion proteins induce deregulation of EphA7 and ERK phosphorylation in human acute leukemias.
  Proc Natl Acad Sci U S A, 104, 14442-14447.  
17332758 J.Lehár, G.R.Zimmermann, A.S.Krueger, R.A.Molnar, J.T.Ledell, A.M.Heilbut, G.F.Short, L.C.Giusti, G.P.Nolan, O.A.Magid, M.S.Lee, A.A.Borisy, B.R.Stockwell, and C.T.Keith (2007).
Chemical combination effects predict connectivity in biological systems.
  Mol Syst Biol, 3, 80.  
17036304 C.S.Page, and P.A.Bates (2006).
Can MM-PBSA calculations predict the specificities of protein kinase inhibitors?
  J Comput Chem, 27, 1990-2007.  
16170358 F.Piu, N.K.Gauthier, and F.Wang (2006).
Beta-arrestin 2 modulates the activity of nuclear receptor RAR beta2 through activation of ERK2 kinase.
  Oncogene, 25, 218-229.  
17114285 M.A.Emrick, T.Lee, P.J.Starkey, M.C.Mumby, K.A.Resing, and N.G.Ahn (2006).
The gatekeeper residue controls autoactivation of ERK2 via a pathway of intramolecular connectivity.
  Proc Natl Acad Sci U S A, 103, 18101-18106.  
15795795 J.N.Peart, and G.J.Gross (2005).
Cardioprotection following adenosine kinase inhibition in rat hearts.
  Basic Res Cardiol, 100, 328-336.  
15937284 M.S.Willis, J.K.Hogan, P.Prabhakar, X.Liu, K.Tsai, Y.Wei, and T.Fox (2005).
Investigation of protein refolding using a fractional factorial screen: a study of reagent effects and interactions.
  Protein Sci, 14, 1818-1826.  
16046538 T.A.Carter, L.M.Wodicka, N.P.Shah, A.M.Velasco, M.A.Fabian, D.K.Treiber, Z.V.Milanov, C.E.Atteridge, W.H.Biggs, P.T.Edeen, M.Floyd, J.M.Ford, R.M.Grotzfeld, S.Herrgard, D.E.Insko, S.A.Mehta, H.K.Patel, W.Pao, C.L.Sawyers, H.Varmus, P.P.Zarrinkar, and D.J.Lockhart (2005).
Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases.
  Proc Natl Acad Sci U S A, 102, 11011-11016.  
14695281 A.N.Hoofnagle, J.W.Stoner, T.Lee, S.S.Eaton, and N.G.Ahn (2004).
Phosphorylation-dependent changes in structure and dynamics in ERK2 detected by SDSL and EPR.
  Biophys J, 86, 395-403.  
15660418 M.Mehrotra, S.M.Krane, K.Walters, and C.Pilbeam (2004).
Differential regulation of platelet-derived growth factor stimulated migration and proliferation in osteoblastic cells.
  J Cell Biochem, 93, 741-752.  
12604539 C.H.Gross, J.D.Parsons, T.H.Grossman, P.S.Charifson, S.Bellon, J.Jernee, M.Dwyer, S.P.Chambers, W.Markland, M.Botfield, and S.A.Raybuck (2003).
Active-site residues of Escherichia coli DNA gyrase required in coupling ATP hydrolysis to DNA supercoiling and amino acid substitutions leading to novobiocin resistance.
  Antimicrob Agents Chemother, 47, 1037-1046.  
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.  
12669025 W.P.Walters, and M.Namchuk (2003).
Designing screens: how to make your hits a hit.
  Nat Rev Drug Discov, 2, 259-266.  
12127491 D.J.Evans, I.A.Maltseva, J.Wu, and S.M.Fleiszig (2002).
Pseudomonas aeruginosa internalization by corneal epithelial cells involves MEK and ERK signal transduction proteins.
  FEMS Microbiol Lett, 213, 73-79.  
11804650 J.M.English, and M.H.Cobb (2002).
Pharmacological inhibitors of MAPK pathways.
  Trends Pharmacol Sci, 23, 40-45.  
12047860 M.Murcko, and P.Caron (2002).
Transforming the genome to drug discovery.
  Drug Discov Today, 7, 583-584.  
12191603 R.A.Engh, and D.Bossemeyer (2002).
Structural aspects of protein kinase control-role of conformational flexibility.
  Pharmacol Ther, 93, 99.  
11836402 T.L.Chang, C.J.Gordon, B.Roscic-Mrkic, C.Power, A.E.Proudfoot, J.P.Moore, and A.Trkola (2002).
Interaction of the CC-chemokine RANTES with glycosaminoglycans activates a p44/p42 mitogen-activated protein kinase-dependent signaling pathway and enhances human immunodeficiency virus type 1 infectivity.
  J Virol, 76, 2245-2254.  
12452429 Y.Shi, and M.Gaestel (2002).
In the cellular garden of forking paths: how p38 MAPKs signal for downstream assistance.
  Biol Chem, 383, 1519-1536.  
11158577 A.N.Hoofnagle, K.A.Resing, E.J.Goldsmith, and N.G.Ahn (2001).
Changes in protein conformational mobility upon activation of extracellular regulated protein kinase-2 as detected by hydrogen exchange.
  Proc Natl Acad Sci U S A, 98, 956-961.  
11470611 P.R.Caron, M.D.Mullican, R.D.Mashal, K.P.Wilson, M.S.Su, and M.A.Murcko (2001).
Chemogenomic approaches to drug discovery.
  Curr Opin Chem Biol, 5, 464-470.  
11449364 U.K.Hanisch, M.Prinz, K.Angstwurm, K.G.Häusler, O.Kann, H.Kettenmann, and J.R.Weber (2001).
The protein tyrosine kinase inhibitor AG126 prevents the massive microglial cytokine induction by pneumococcal cell walls.
  Eur J Immunol, 31, 2104-2115.  
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.  
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.  
10421767 C.A.Hall-Jackson, P.A.Eyers, P.Cohen, M.Goedert, F.T.Boyle, N.Hewitt, H.Plant, and P.Hedge (1999).
Paradoxical activation of Raf by a novel Raf inhibitor.
  Chem Biol, 6, 559-568.  
10508788 S.Bellon, M.J.Fitzgibbon, T.Fox, H.M.Hsiao, and K.P.Wilson (1999).
The structure of phosphorylated p38gamma is monomeric and reveals a conserved activation-loop conformation.
  Structure, 7, 1057-1065.
PDB code: 1cm8
10360180 T.Schindler, F.Sicheri, A.Pico, A.Gazit, A.Levitzki, and J.Kuriyan (1999).
Crystal structure of Hck in complex with a Src family-selective tyrosine kinase inhibitor.
  Mol Cell, 3, 639-648.
PDB code: 1qcf
10467133 Y.Liu, A.Bishop, L.Witucki, B.Kraybill, E.Shimizu, J.Tsien, J.Ubersax, J.Blethrow, D.O.Morgan, and K.M.Shokat (1999).
Structural basis for selective inhibition of Src family kinases by PP1.
  Chem Biol, 6, 671-678.  
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.