Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors

Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13919-24. doi: 10.1073/pnas.241410198. Epub 2001 Nov 6.

Abstract

The peroxisome proliferator-activated receptors (PPARs) are transcriptional regulators of glucose, lipid, and cholesterol metabolism. We report the x-ray crystal structure of the ligand binding domain of PPAR alpha (NR1C1) as a complex with the agonist ligand GW409544 and a coactivator motif from the steroid receptor coactivator 1. Through comparison of the crystal structures of the ligand binding domains of the three human PPARs, we have identified molecular determinants of subtype selectivity. A single amino acid, which is tyrosine in PPAR alpha and histidine in PPAR gamma, imparts subtype selectivity for both thiazolidinedione and nonthiazolidinedione ligands. The availability of high-resolution cocrystal structures of the three PPAR subtypes will aid the design of drugs for the treatments of metabolic and cardiovascular diseases.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Crystallography, X-Ray
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Sequence Data
  • Molecular Structure
  • Oxazoles / chemistry*
  • Protein Structure, Tertiary
  • Receptors, Cytoplasmic and Nuclear / agonists
  • Receptors, Cytoplasmic and Nuclear / chemistry*
  • Transcription Factors / agonists
  • Transcription Factors / chemistry*
  • Tyrosine / analogs & derivatives*
  • Tyrosine / chemistry*

Substances

  • GW 409544
  • Ligands
  • Oxazoles
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • Tyrosine

Associated data

  • PDB/1K74
  • PDB/1K7L