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

Mutation of glutamic acid 282 of PPARα 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 mPPARα and...

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Bibliographic Details
Published in:FEBS letters 1999-12, Vol.463 (3), p.205-210
Main Authors: Causevic, Mirsada, Wolf, C.Roland, Palmer, Colin N.A.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Amino Acids - chemistry
Animals
CPA, cis-parinaric acid
Diabetes
EPA, eicosapentanoic acid
ER, oestrogen receptor
Escherichia coli
Fatty acid
Fatty Acids, Unsaturated - chemistry
Fluorescence
Fluorescent Dyes - chemistry
Gene Expression
Glutamic Acid - chemistry
Humans
LBD, ligand binding domain
Ligands
Mice
Molecular Sequence Data
Mutation
Nuclear receptor
Peroxisome proliferator
PPAR, peroxisome proliferator activated receptor
RAR, retinoic acid receptor
Receptors, Cytoplasmic and Nuclear - chemistry
Receptors, Cytoplasmic and Nuclear - genetics
RXR, retinoid X receptor
Sequence Alignment
Thiazolidinedione
TR, thyroid hormone receptor
Transcription Factors - chemistry
Transcription Factors - genetics
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Summary:Mutation of glutamic acid 282 of PPARα 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 mPPARα and hPPARγ for the fluorescent fatty acid, cis-parinaric acid and that the mutant hPPARγ 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.
ISSN:0014-5793
1873-3468
DOI:10.1016/S0014-5793(99)01618-X