Structural basis for autoinhibition of Notch

Nat Struct Mol Biol. 2007 Apr;14(4):295-300. doi: 10.1038/nsmb1227. Epub 2007 Apr 1.


Notch receptors transmit signals between adjacent cells. Signaling is initiated when ligand binding induces metalloprotease cleavage of Notch within an extracellular negative regulatory region (NRR). We present here the X-ray structure of the human NOTCH2 NRR, which adopts an autoinhibited conformation. Extensive interdomain interactions within the NRR bury the metalloprotease site, showing that a substantial conformational movement is necessary to expose this site during activation by ligand. Leukemia-associated mutations in NOTCH1 probably release autoinhibition by destabilizing the conserved hydrophobic core of the NRR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Crystallography, X-Ray
  • Genes, Reporter
  • Humans
  • Models, Molecular
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Receptor, Notch2 / antagonists & inhibitors*
  • Receptor, Notch2 / chemistry*
  • Structure-Activity Relationship


  • Receptor, Notch2

Associated data

  • PDB/2OO4