Substitution of a conserved amino acid residue alters the ligand binding properties of peroxisome proliferator activated receptors

FEBS Lett. 1999 Dec 17;463(3):205-10. doi: 10.1016/s0014-5793(99)01618-x.

Abstract

Mutation of glutamic acid 282 of PPARalpha to glycine has been shown to result in an increased EC(50) for a wide variety of PPAR activating compounds. This has suggested that mutant receptor has a reduced ability to bind ligand. In this study we show that this mutation reduces the affinity of mPPARalpha and hPPARgamma for the fluorescent fatty acid, cis-parinaric acid and that the mutant hPPARgamma protein has a reduced affinity for the radiolabelled compound, SB236636. These data confirm the role of this glutamic acid in ligand binding and support recent crystal structure observations regarding a proposed novel mode of ligand entry into the PPAR ligand binding cavities.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acids / chemistry*
  • Animals
  • Escherichia coli
  • Fatty Acids, Unsaturated / chemistry
  • Fluorescent Dyes / chemistry
  • Gene Expression
  • Glutamic Acid / chemistry
  • Humans
  • Ligands
  • Mice
  • Molecular Sequence Data
  • Mutation
  • Receptors, Cytoplasmic and Nuclear / chemistry*
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Sequence Alignment
  • Transcription Factors / chemistry*
  • Transcription Factors / genetics

Substances

  • Amino Acids
  • Fatty Acids, Unsaturated
  • Fluorescent Dyes
  • Ligands
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • Glutamic Acid
  • parinaric acid