Structure of a complex between Nedd8 and the Ulp/Senp protease family member Den1

J Mol Biol. 2005 Jan 7;345(1):141-51. doi: 10.1016/j.jmb.2004.10.022.


The Nedd8 conjugation pathway is conserved from yeast to humans and is essential in many organisms. Nedd8 is conjugated to cullin proteins in a process that alters SCF E3 ubiquitin ligase activity, and it is presumed that Nedd8 deconjugation would reverse these effects. We now report the X-ray structures of the human Nedd8-specific protease, Den1, in a complex with the inhibitor Nedd8 aldehyde, thus revealing a model for the tetrahedral transition state intermediate generated during proteolysis. Although Den1 is closely related to the SUMO-specific protease family (Ulp/Senp family), structural analysis of the interface suggests determinants involved in Nedd8 selectivity by Den1 over other ubiquitin-like family members and suggests how the Ulp/Senp architecture has been modified to interact with different ubiquitin-like modifiers.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Crystallography, X-Ray
  • Endopeptidases / chemistry*
  • Endopeptidases / genetics
  • Endopeptidases / metabolism
  • Humans
  • Macromolecular Substances
  • Models, Molecular
  • Molecular Sequence Data
  • NEDD8 Protein
  • Protein Binding
  • Protein Conformation*
  • Sequence Alignment
  • Ubiquitins / chemistry*
  • Ubiquitins / genetics
  • Ubiquitins / metabolism


  • Macromolecular Substances
  • NEDD8 Protein
  • NEDD8 protein, human
  • Ubiquitins
  • Endopeptidases
  • SENP8 protein, human

Associated data

  • PDB/1XT9