PDBsum entry 3c9w

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protein ligands links
Transferase PDB id
Protein chains
336 a.a. *
HMY ×2
Waters ×257
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Crystal structure of erk-2 with hypothemycin covalently bound
Structure: Mitogen-activated protein kinase 1. Chain: a, b. Synonym: extracellular signal-regulated kinase 2, erk-2, mitogen-activated protein kinase 2, map kinase 2, mapk 2, p42-mapk, ert1. Engineered: yes
Source: Rattus norvegicus. Rat. Organism_taxid: 10116. Gene: erk2. Expressed in: escherichia coli. Expression_system_taxid: 562.
2.50Å     R-factor:   0.201     R-free:   0.274
Authors: R.J.Rosenfeld
Key ref: G.Rastelli et al. (2008). Molecular modeling and crystal structure of ERK2-hypothemycin complexes. J Struct Biol, 164, 18-23. PubMed id: 18571434 DOI: 10.1016/j.jsb.2008.05.002
18-Feb-08     Release date:   08-Jul-08    
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Protein chains
Pfam   ArchSchema ?
P63086  (MK01_RAT) -  Mitogen-activated protein kinase 1
358 a.a.
336 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     mitotic spindle   21 terms 
  Biological process     intracellular signal transduction   40 terms 
  Biochemical function     nucleotide binding     15 terms  


DOI no: 10.1016/j.jsb.2008.05.002 J Struct Biol 164:18-23 (2008)
PubMed id: 18571434  
Molecular modeling and crystal structure of ERK2-hypothemycin complexes.
G.Rastelli, R.Rosenfeld, R.Reid, D.V.Santi.
Resorcylic acid lactones containing a cis-enone-such as hypothemycin-are susceptible to Michael addition reactions and are potent and specific inhibitors of about 45 of the known Ser/Thr/Tyr protein kinases. These inhibitors bind reversibly, and then form a covalent adduct with a completely conserved cysteine in the ATP binding site of their target kinases. As a paradigm for the structures of the cis-enone resorcylic acid lactone complexes with this subset of kinases, we have modeled the structure of ERK2-hypothemycin reversible and covalent complexes using docking and extended molecular dynamics simulations. Subsequently, we determined the 2.5A resolution crystal structure of the complex that was in excellent accord with the modeled structure. The results were used to discuss structure-activity relationships, and provide a structural template for the development of irreversible inhibitors that complement the ATP binding site of kinases.

Literature references that cite this PDB file's key reference

  PubMed id Reference
21110380 J.L.Yap, S.Worlikar, A.D.Mackerell, P.Shapiro, and S.Fletcher (2011).
Small-Molecule Inhibitors of the ERK Signaling Pathway: Towards Novel Anticancer Therapeutics.
  ChemMedChem, 6, 38-48.  
20306284 A.Del Rio, M.Sgobba, M.D.Parenti, G.Degliesposti, R.Forestiero, C.Percivalle, P.F.Conte, M.Freccero, and G.Rastelli (2010).
A computational workflow for the design of irreversible inhibitors of protein kinases.
  J Comput Aided Mol Des, 24, 183-194.  
20623569 S.Barluenga, R.Jogireddy, G.K.Koripelly, and N.Winssinger (2010).
In vivo efficacy of natural product-inspired irreversible kinase inhibitors.
  Chembiochem, 11, 1692-1699.  
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