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

Abstract

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.

• Authors: H Eric Xu, Thomas B Stanley, Valerie G Montana, Millard H Lambert, Barry G Shearer, Jeffery E Cobb, David D McKee, Cristin M Galardi, Kelli D Plunket, Robert T Nolte, Derek J Parks, John T Moore, Steven A Kliewer, Timothy M Willson, Julie B Stimmel
• Journal: Nature (Nature) Vol. 415 Issue 6873 Pg. 813-7 (Feb 14 2002) ISSN: 0028-0836 [Print] England
• PMID: 11845213 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• DNA-Binding Proteins
• GW 409544
• GW 6471
• Ligands
• NCOR2 protein, human
• Nuclear Receptor Co-Repressor 2
• Oxazoles
• Receptors, Cytoplasmic and Nuclear
• Repressor Proteins
• Transcription Factors
• Tyrosine

Topics

• Amino Acid Motifs
• Amino Acid Sequence
• Binding Sites
• Crystallography, X-Ray
• DNA-Binding Proteins (chemistry, metabolism)
• Humans
• Inhibitory Concentration 50
• Ligands
• Models, Molecular
• Molecular Sequence Data
• Nuclear Receptor Co-Repressor 2
• Oxazoles (metabolism, pharmacology)
• Protein Binding (drug effects)
• Protein Structure, Secondary
• Protein Structure, Tertiary
• Receptors, Cytoplasmic and Nuclear (agonists, antagonists & inhibitors, chemistry, metabolism)
• Repressor Proteins (chemistry, metabolism)
• Sequence Alignment
• Structure-Activity Relationship
• Transcription Factors (agonists, antagonists & inhibitors, chemistry, metabolism)
• Tyrosine (analogs & derivatives, metabolism, pharmacology)