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

• Published in: Nature (London) 2002-02, Vol.415 (6873), p.813-817
• Main Authors: Xu, H Eric, Stanley, Thomas B, Montana, Valerie G, Lambert, Millard H, Shearer, Barry G, Cobb, Jeffery E, McKee, David D, Galardi, Cristin M, Plunket, Kelli D, Nolte, Robert T, Parks, Derek J, Moore, John T, Kliewer, Steven A, Willson, Timothy M, Stimmel, Julie B
• Format: Article
• Language: English
• Subjects: Amino Acid Motifs; Amino Acid Sequence; Binding Sites; Chemistry; Crystallography; Crystallography, X-Ray; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - metabolism; Genetics; Humans; Inhibitory Concentration 50; Leukemia; 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; Thyroid; Transcription Factors - agonists; Transcription Factors - antagonists & inhibitors; Transcription Factors - chemistry; Transcription Factors - metabolism; Tyrosine - analogs & derivatives; Tyrosine - metabolism; Tyrosine - pharmacology
• ISSN: 0028-0836; 1476-4687
• 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.