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Bypassing a kinase activity with an ATP-competitive drug.

Unfolded proteins in the endoplasmic reticulum cause trans-autophosphorylation of the bifunctional transmembrane kinase Ire1, which induces its endoribonuclease activity. The endoribonuclease initiates nonconventional splicing of HAC1 messenger RNA to trigger the unfolded-protein response (UPR). We explored the role of Ire1's kinase domain by sensitizing it through site-directed mutagenesis to the ATP-competitive inhibitor 1NM-PP1. Paradoxically, rather than being inhibited by 1NM-PP1, drug-sensitized Ire1 mutants required 1NM-PP1 as a cofactor for activation. In the presence of 1NM-PP1, drug-sensitized Ire1 bypassed mutations that inactivate its kinase activity and induced a full UPR. Thus, rather than through phosphorylation per se, a conformational change in the kinase domain triggered by occupancy of the active site with a ligand leads to activation of all known downstream functions.

Pubmed ID: 14564015


  • Papa FR
  • Zhang C
  • Shokat K
  • Walter P


Science (New York, N.Y.)

Publication Data

November 28, 2003

Associated Grants

  • Agency: NIAID NIH HHS, Id: AI44009
  • Agency: NIGMS NIH HHS, Id: GM32384

Mesh Terms

  • Adenosine Diphosphate
  • Adenosine Triphosphate
  • Basic-Leucine Zipper Transcription Factors
  • Binding Sites
  • Binding, Competitive
  • Cytosol
  • Dithiothreitol
  • Endoplasmic Reticulum
  • Endoribonucleases
  • Enzyme Activation
  • Ligands
  • Membrane Glycoproteins
  • Models, Biological
  • Mutagenesis, Site-Directed
  • Phosphorylation
  • Protein Conformation
  • Protein Folding
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases
  • Pyrazoles
  • Pyrimidines
  • RNA Splicing
  • RNA, Messenger
  • Repressor Proteins
  • Saccharomyces cerevisiae Proteins
  • Signal Transduction
  • Structure-Activity Relationship
  • Substrate Specificity
  • Transcription Factors
  • Up-Regulation