Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma

Nature. 1998 Sep 10;395(6698):137-43. doi: 10.1038/25931.


The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a ligand-dependent transcription factor that is important in adipocyte differentiation and glucose homeostasis and which depends on interactions with co-activators, including steroid receptor co-activating factor-1 (SRC-1). Here we present the X-ray crystal structure of the human apo-PPAR-gamma ligand-binding domain (LBD), at 2.2 A resolution; this structure reveals a large binding pocket, which may explain the diversity of ligands for PPAR-gamma. We also describe the ternary complex containing the PPAR-gamma LBD, the antidiabetic ligand rosiglitazone (BRL49653), and 88 amino acids of human SRC-1 at 2.3 A resolution. Glutamate and lysine residues that are highly conserved in LBDs of nuclear receptors form a 'charge clamp' that contacts backbone atoms of the LXXLL helices of SRC-1. These results, together with the observation that two consecutive LXXLL motifs of SRC-1 make identical contacts with both subunits of a PPAR-gamma homodimer, suggest a general mechanism for the assembly of nuclear receptors with co-activators.

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Cloning, Molecular
  • Conserved Sequence
  • Crystallography, X-Ray
  • Escherichia coli
  • Histone Acetyltransferases
  • Humans
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / metabolism
  • Ligands
  • Macromolecular Substances
  • Molecular Sequence Data
  • Nuclear Receptor Coactivator 1
  • Protein Conformation
  • Protein Structure, Tertiary
  • Receptors, Cytoplasmic and Nuclear / chemistry*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Rosiglitazone
  • Structure-Activity Relationship
  • Thiazoles / chemistry
  • Thiazoles / metabolism
  • Thiazolidinediones*
  • Transcription Factors / chemistry*
  • Transcription Factors / metabolism
  • Transcriptional Activation


  • Hypoglycemic Agents
  • Ligands
  • Macromolecular Substances
  • Receptors, Cytoplasmic and Nuclear
  • Thiazoles
  • Thiazolidinediones
  • Transcription Factors
  • Rosiglitazone
  • Histone Acetyltransferases
  • NCOA1 protein, human
  • Nuclear Receptor Coactivator 1

Associated data

  • PDB/1PRG
  • PDB/2PRG