PDBsum entry 2clq

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Transferase PDB id
Protein chain
263 a.a. *
STU ×2
Waters ×149
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Structure of mitogen-activated protein kinase kinase kinase 5
Structure: Mitogen-activated protein kinase kinase kinase 5. Chain: a, b. Fragment: kinase domain residues 659-951. Synonym: map3k5, mapk/erk kinase kinase 5, mek kinase 5, me apoptosis signal-regulating kinase 1, ask-1. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008.
Biol. unit: Dimer (from PDB file)
2.30Å     R-factor:   0.204     R-free:   0.257
Authors: G.Bunkoczi,E.Salah,O.Fedorov,A.Pike,O.Gileadi,F.Von Delft, C.Arrowsmith,A.Edwards,M.Sundstrom,J.Weigelt,S.Knapp
Key ref:
G.Bunkoczi et al. (2007). Structural and functional characterization of the human protein kinase ASK1. Structure, 15, 1215-1226. PubMed id: 17937911 DOI: 10.1016/j.str.2007.08.011
28-Apr-06     Release date:   09-May-06    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
Q99683  (M3K5_HUMAN) -  Mitogen-activated protein kinase kinase kinase 5
1374 a.a.
263 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - Mitogen-activated protein kinase kinase 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!
  Biological process     protein phosphorylation   1 term 
  Biochemical function     transferase activity, transferring phosphorus-containing groups     4 terms  


DOI no: 10.1016/j.str.2007.08.011 Structure 15:1215-1226 (2007)
PubMed id: 17937911  
Structural and functional characterization of the human protein kinase ASK1.
G.Bunkoczi, E.Salah, P.Filippakopoulos, O.Fedorov, S.Müller, F.Sobott, S.A.Parker, H.Zhang, W.Min, B.E.Turk, S.Knapp.
Apoptosis signal-regulating kinase 1 (ASK1) plays an essential role in stress and immune response and has been linked to the development of several diseases. Here, we present the structure of the human ASK1 catalytic domain in complex with staurosporine. Analytical ultracentrifugation (AUC) and crystallographic analysis showed that ASK1 forms a tight dimer (K(d) approximately 0.2 microM) interacting in a head-to-tail fashion. We found that the ASK1 phosphorylation motifs differ from known ASK1 phosphorylation sites but correspond well to autophosphorylation sites identified by mass spectrometry. Reporter gene assays showed that all three identified in vitro autophosphorylation sites (Thr813, Thr838, Thr842) regulate ASK1 signaling, but site-directed mutants showed catalytic activities similar to wild-type ASK1, suggesting a regulatory mechanism independent of ASK1 kinase activity. The determined high-resolution structure of ASK1 and identified ATP mimetic inhibitors will provide a first starting point for the further development of selective inhibitors.
  Selected figure(s)  
Figure 2.
Figure 2. Binding of Stauroporine
Main interacting active site residues with the ATP competitive inhibitor staurosporine are shown in ball-and-stick representation. Hydrogen bonds formed between the ligand and the protein are shown as dotted lines.
Figure 3.
Figure 3. Activation Segment of ASK1
(A) Interaction between the helix αC and the DFG motif. Hydrogen bonds are shown as dotted lines.
(B) Hydrogen bond network stabilizing N- and C-terminal portion of the activation segment and link the ASK1 activation segment to the catalytic loop residue Arg802.
(C) Interaction stabilizing the activation segment in the active and phosphorylated kinase PAK4 (Eswaran et al., 2007).
  The above figures are reprinted from an Open Access publication published by Cell Press: Structure (2007, 15, 1215-1226) copyright 2007.  
  Figures were selected by the author.  
    Author's comment    
  An animated version of the structure (active Isee) as well as detailed description of material and methods is also available on our website:  

Literature references that cite this PDB file's key reference

  PubMed id Reference
22197930 M.S.Stark, S.L.Woods, M.G.Gartside, V.F.Bonazzi, K.Dutton-Regester, L.G.Aoude, D.Chow, C.Sereduk, N.M.Niemi, N.Tang, J.J.Ellis, J.Reid, V.Zismann, S.Tyagi, D.Muzny, I.Newsham, Y.Wu, J.M.Palmer, T.Pollak, D.Youngkin, B.R.Brooks, C.Lanagan, C.W.Schmidt, B.Kobe, J.P.MacKeigan, H.Yin, K.M.Brown, R.Gibbs, J.Trent, and N.K.Hayward (2012).
Frequent somatic mutations in MAP3K5 and MAP3K9 in metastatic melanoma identified by exome sequencing.
  Nat Genet, 44, 165-169.  
20336234 O.A.Gani, and R.A.Engh (2010).
Protein kinase inhibition of clinically important staurosporine analogues.
  Nat Prod Rep, 27, 489-498.  
20685651 S.Karassek, C.Berghaus, M.Schwarten, C.G.Goemans, N.Ohse, G.Kock, K.Jockers, S.Neumann, S.Gottfried, C.Herrmann, R.Heumann, and R.Stoll (2010).
Ras homolog enriched in brain (Rheb) enhances apoptotic signaling.
  J Biol Chem, 285, 33979-33991.
PDB code: 2l0x
19489729 A.Edwards (2009).
Large-scale structural biology of the human proteome.
  Annu Rev Biochem, 78, 541-568.  
19389260 K.Hattori, I.Naguro, C.Runchel, and H.Ichijo (2009).
The roles of ASK family proteins in stress responses and diseases.
  Cell Commun Signal, 7, 9.  
19287004 L.Yu, W.Min, Y.He, L.Qin, H.Zhang, A.M.Bennett, and H.Chen (2009).
JAK2 and SHP2 Reciprocally Regulate Tyrosine Phosphorylation and Stability of Proapoptotic Protein ASK1.
  J Biol Chem, 284, 13481-13488.  
19789335 T.Kitamura, Y.Fukuyo, M.Inoue, N.T.Horikoshi, M.Shindoh, B.E.Rogers, A.Usheva, and N.Horikoshi (2009).
Mutant p53 disrupts the stress MAPK activation circuit induced by ASK1-dependent stabilization of Daxx.
  Cancer Res, 69, 7681-7688.  
19001375 X.Song, S.Coffa, H.Fu, and V.V.Gurevich (2009).
How Does Arrestin Assemble MAPKs into a Signaling Complex?
  J Biol Chem, 284, 685-695.  
18267130 B.D.Marsden, and S.Knapp (2008).
Doing more than just the structure-structural genomics in kinase drug discovery.
  Curr Opin Chem Biol, 12, 40-45.  
18439900 D.M.Gwinn, D.B.Shackelford, D.F.Egan, M.M.Mihaylova, A.Mery, D.S.Vasquez, B.E.Turk, and R.J.Shaw (2008).
AMPK phosphorylation of raptor mediates a metabolic checkpoint.
  Mol Cell, 30, 214-226.  
18282486 J.Weigelt, L.D.McBroom-Cerajewski, M.Schapira, Y.Zhao, C.H.Arrowsmith, and C.H.Arrowmsmith (2008).
Structural genomics and drug discovery: all in the family.
  Curr Opin Chem Biol, 12, 32-39.  
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.