Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARalpha

Nature. 2002 Feb 14;415(6873):813-7. doi: 10.1038/415813a.


Repression of gene transcription by nuclear receptors is mediated by interactions with co-repressor proteins such as SMRT and N-CoR, which in turn recruit histone deacetylases to the chromatin. Aberrant interactions between nuclear receptors and co-repressors contribute towards acute promyelocytic leukaemia and thyroid hormone resistance syndrome. The binding of co-repressors to nuclear receptors occurs in the unliganded state, and can be stabilized by antagonists. Here we report the crystal structure of a ternary complex containing the peroxisome proliferator-activated receptor-alpha ligand-binding domain bound to the antagonist GW6471 and a SMRT co-repressor motif. In this structure, the co-repressor motif adopts a three-turn alpha-helix that prevents the carboxy-terminal activation helix (AF-2) of the receptor from assuming the active conformation. Binding of the co-repressor motif is further reinforced by the antagonist, which blocks the AF-2 helix from adopting the active position. Biochemical analyses and structure-based mutagenesis indicate that this mode of co-repressor binding is highly conserved across nuclear receptors.

Publication types

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

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Binding Sites
  • Crystallography, X-Ray
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / metabolism*
  • Humans
  • Inhibitory Concentration 50
  • Ligands
  • Models, Molecular
  • Molecular Sequence Data
  • Nuclear Receptor Co-Repressor 2
  • Oxazoles / metabolism
  • Oxazoles / pharmacology*
  • Protein Binding / drug effects
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Receptors, Cytoplasmic and Nuclear / agonists
  • Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors*
  • Receptors, Cytoplasmic and Nuclear / chemistry*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Repressor Proteins / chemistry*
  • Repressor Proteins / metabolism*
  • Sequence Alignment
  • Structure-Activity Relationship
  • Transcription Factors / agonists
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / chemistry*
  • Transcription Factors / metabolism
  • Tyrosine / analogs & derivatives
  • Tyrosine / metabolism
  • Tyrosine / pharmacology*


  • DNA-Binding Proteins
  • GW 409544
  • GW 6471
  • Ligands
  • NCOR2 protein, human
  • Nuclear Receptor Co-Repressor 2
  • Oxazoles
  • Receptors, Cytoplasmic and Nuclear
  • Repressor Proteins
  • Transcription Factors
  • Tyrosine

Associated data

  • PDB/1K7L
  • PDB/1KQQ