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PDBsum entry 1cm8

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protein ligands metals Protein-protein interface(s) links
Transferase PDB id
1cm8
Jmol
Contents
Protein chain
329 a.a. *
Ligands
ANP ×2
Metals
_MG ×4
Waters ×186
* Residue conservation analysis
PDB id:
1cm8
Name: Transferase
Title: Phosphorylated map kinase p38-gamma
Structure: Phosphorylated map kinase p38-gamma. Chain: a, b. Synonym: stress-activated protein kinase-3, erk6, erk5. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
2.40Å     R-factor:   0.232     R-free:   0.283
Authors: S.Bellon,M.J.Fitzgibbon,T.Fox,H.M.Hsiao,K.P.Wilson
Key ref:
S.Bellon et al. (1999). The structure of phosphorylated p38gamma is monomeric and reveals a conserved activation-loop conformation. Structure Fold Des, 7, 1057-1065. PubMed id: 10508788 DOI: 10.1016/S0969-2126(99)80173-7
Date:
17-May-99     Release date:   17-May-00    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P53778  (MK12_HUMAN) -  Mitogen-activated protein kinase 12
Seq:
Struc:
367 a.a.
329 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.2.7.11.24  - Mitogen-activated protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
ATP
+ protein
=
ADP
Bound ligand (Het Group name = ANP)
matches with 81.00% similarity
+ phosphoprotein
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   6 terms 
  Biological process     response to stress   18 terms 
  Biochemical function     nucleotide binding     11 terms  

 

 
    reference    
 
 
DOI no: 10.1016/S0969-2126(99)80173-7 Structure Fold Des 7:1057-1065 (1999)
PubMed id: 10508788  
 
 
The structure of phosphorylated p38gamma is monomeric and reveals a conserved activation-loop conformation.
S.Bellon, M.J.Fitzgibbon, T.Fox, H.M.Hsiao, K.P.Wilson.
 
  ABSTRACT  
 
BACKGROUND: Mitogen-activated protein (MAP) kinases mediate the cellular response to stimuli such as pro-inflammatory cytokines and environmental stress. P38gamma is a new member of the MAP kinase family, and is expressed at its highest levels in skeletal muscle. P38gamma is 63% identical in sequence to P38alpha. The structure of P38alpha MAP kinase has been determined in the apo, unphosphorylated, inactive form. The structures of apo unphosphorylated ERK2, a related MAP kinase, and apo phosphorylated ERK2 have also been determined. RESULTS: We have determined the structure of doubly phosphorylated P38gamma in complex with an ATP analog by X-ray crystallography. This is the first report of a structure of an activated kinase in the P38 subfamily, and the first bound to a nucleotide. P38gamma residue phosphoryl-Thr183 forms hydrogen bonds with five basic amino acids, and these interactions induce an interdomain rotation. The conformation of the activation loop of P38gamma is almost identical to that observed in the structure of activated ERK2. However, unlike ERK2, the crystal structure and solution studies indicate that activated P38gamma exists as a monomer. CONCLUSIONS: Interactions mediated by phosphoryl-Thr183 induce structural changes that direct the domains and active-site residues of P38gamma into a conformation consistent with catalytic activity. The conformation of the phosphorylation loop is likely to be similar in all activated MAP kinases, but not all activated MAP kinases form dimers.
 
  Selected figure(s)  
 
Figure 4.
Figure 4. Stereoview of AMP-PNP. All major interactions with protein sidechains are indicated by dashed gray lines. The bound Mg2+ ions are indicated by black spheres. The phosphate atoms are shown in purple. Met109 can be seen behind the adenine base, blocking the hydrophobic pocket. Water molecules have been removed for clarity.
 
  The above figure is reprinted by permission from Cell Press: Structure Fold Des (1999, 7, 1057-1065) copyright 1999.  
  Figure was selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21409189 S.Y.Lu, Y.J.Jiang, J.W.Zou, and T.X.Wu (2011).
Dissection of the difference between the group I metal ions in inhibiting GSK3β: a computational study.
  Phys Chem Chem Phys, 13, 7014-7023.  
20626350 A.Cuadrado, and A.R.Nebreda (2010).
Mechanisms and functions of p38 MAPK signalling.
  Biochem J, 429, 403-417.  
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
20637424 Y.W.Ng, D.Raghunathan, P.M.Chan, Y.Baskaran, D.J.Smith, C.H.Lee, C.Verma, and E.Manser (2010).
Why an A-loop phospho-mimetic fails to activate PAK1: understanding an inaccessible kinase state by molecular dynamics simulations.
  Structure, 18, 879-890.  
19492062 A.A.Santos, C.M.Carvalho, L.H.Florentino, H.J.Ramos, and E.P.Fontes (2009).
Conserved threonine residues within the A-loop of the receptor NIK differentially regulate the kinase function required for antiviral signaling.
  PLoS One, 4, e5781.  
19361221 A.G.Turjanski, G.Hummer, and J.S.Gutkind (2009).
How mitogen-activated protein kinases recognize and phosphorylate their targets: A QM/MM study.
  J Am Chem Soc, 131, 6141-6148.  
19324872 P.R.Mittelstadt, H.Yamaguchi, E.Appella, and J.D.Ashwell (2009).
T cell receptor-mediated activation of p38{alpha} by mono-phosphorylation of the activation loop results in altered substrate specificity.
  J Biol Chem, 284, 15469-15474.  
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.  
19622861 S.B.Patel, P.M.Cameron, S.J.O'Keefe, B.Frantz-Wattley, J.Thompson, E.A.O'Neill, T.Tennis, L.Liu, J.W.Becker, and G.Scapin (2009).
The three-dimensional structure of MAP kinase p38beta: different features of the ATP-binding site in p38beta compared with p38alpha.
  Acta Crystallogr D Biol Crystallogr, 65, 777-785.
PDB codes: 3gc7 3gc8 3gc9
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
18184370 D.Muyllaert, A.Kremer, T.Jaworski, P.Borghgraef, H.Devijver, S.Croes, I.Dewachter, and F.Van Leuven (2008).
Glycogen synthase kinase-3beta, or a link between amyloid and tau pathology?
  Genes Brain Behav, 7, 57-66.  
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.  
18212044 Y.Murakami, K.Tatebayashi, and H.Saito (2008).
Two adjacent docking sites in the yeast Hog1 mitogen-activated protein (MAP) kinase differentially interact with the Pbs2 MAP kinase kinase and the Ptp2 protein tyrosine phosphatase.
  Mol Cell Biol, 28, 2481-2494.  
17694525 D.Kuhn, N.Weskamp, E.Hüllermeier, and G.Klebe (2007).
Functional Classification of Protein Kinase Binding Sites Using Cavbase.
  ChemMedChem, 2, 1432-1447.  
17912359 J.D.Knight, B.Qian, D.Baker, and R.Kothary (2007).
Conservation, variability and the modeling of active protein kinases.
  PLoS ONE, 2, e982.  
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.  
18060821 Y.Zhu, H.Li, C.Long, L.Hu, H.Xu, L.Liu, S.Chen, D.C.Wang, and F.Shao (2007).
Structural insights into the enzymatic mechanism of the pathogenic MAPK phosphothreonine lyase.
  Mol Cell, 28, 899-913.
PDB codes: 2p1w 2q8y
17242196 Z.Miyake, M.Takekawa, Q.Ge, and H.Saito (2007).
Activation of MTK1/MEKK4 by GADD45 through induced N-C dissociation and dimerization-mediated trans autophosphorylation of the MTK1 kinase domain.
  Mol Cell Biol, 27, 2765-2776.  
16628247 E.S.Groban, A.Narayanan, and M.P.Jacobson (2006).
Conformational changes in protein loops and helices induced by post-translational phosphorylation.
  PLoS Comput Biol, 2, e32.  
16799472 J.D.Ashwell (2006).
The many paths to p38 mitogen-activated protein kinase activation in the immune system.
  Nat Rev Immunol, 6, 532-540.  
16148006 C.Tárrega, P.Ríos, R.Cejudo-Marín, C.Blanco-Aparicio, L.van den Berk, J.Schepens, W.Hendriks, L.Tabernero, and R.Pulido (2005).
ERK2 shows a restrictive and locally selective mechanism of recognition by its tyrosine phosphatase inactivators not shared by its activator MEK1.
  J Biol Chem, 280, 37885-37894.  
15735648 J.M.Salvador, P.R.Mittelstadt, T.Guszczynski, T.D.Copeland, H.Yamaguchi, E.Appella, A.J.Fornace, and J.D.Ashwell (2005).
Alternative p38 activation pathway mediated by T cell receptor-proximal tyrosine kinases.
  Nat Immunol, 6, 390-395.  
15879519 S.H.Millson, A.W.Truman, V.King, C.Prodromou, L.H.Pearl, and P.W.Piper (2005).
A two-hybrid screen of the yeast proteome for Hsp90 interactors uncovers a novel Hsp90 chaperone requirement in the activity of a stress-activated mitogen-activated protein kinase, Slt2p (Mpk1p).
  Eukaryot Cell, 4, 849-860.  
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.  
15284239 R.Diskin, N.Askari, R.Capone, D.Engelberg, and O.Livnah (2004).
Active mutants of the human p38alpha mitogen-activated protein kinase.
  J Biol Chem, 279, 47040-47049.  
15068802 T.Lee, A.N.Hoofnagle, Y.Kabuyama, J.Stroud, X.Min, E.J.Goldsmith, L.Chen, K.A.Resing, and N.G.Ahn (2004).
Docking motif interactions in MAP kinases revealed by hydrogen exchange mass spectrometry.
  Mol Cell, 14, 43-55.  
12615961 B.W.Doble, and J.R.Woodgett (2003).
GSK-3: tricks of the trade for a multi-tasking kinase.
  J Cell Sci, 116, 1175-1186.  
14506247 F.L.Chou, J.M.Hill, J.C.Hsieh, J.Pouyssegur, A.Brunet, A.Glading, F.Uberall, J.W.Ramos, M.H.Werner, and M.H.Ginsberg (2003).
PEA-15 binding to ERK1/2 MAPKs is required for its modulation of integrin activation.
  J Biol Chem, 278, 52587-52597.  
12637550 M.Bell, and D.Engelberg (2003).
Phosphorylation of Tyr-176 of the yeast MAPK Hog1/p38 is not vital for Hog1 biological activity.
  J Biol Chem, 278, 14603-14606.  
12191603 R.A.Engh, and D.Bossemeyer (2002).
Structural aspects of protein kinase control-role of conformational flexibility.
  Pharmacol Ther, 93, 99.  
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.