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

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

doi:10.1038/415813a

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

Nature. 2002 Feb 14;415(6873):813-7. doi: 10.1038/415813a.

Authors

H Eric Xu¹, 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

Affiliation

¹ Nuclear Receptor Discovery Research, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. [email protected]

PMID: 11845213
DOI: 10.1038/415813a

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.

Publication types

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

MeSH terms

Amino Acid Motifs
Amino Acid Sequence
Binding Sites
Crystallography, X-Ray
DNA-Binding Proteins / chemistry*
DNA-Binding Proteins / metabolism*
Humans
Inhibitory Concentration 50
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
Transcription Factors / agonists
Transcription Factors / antagonists & inhibitors*
Transcription Factors / chemistry*
Transcription Factors / metabolism
Tyrosine / analogs & derivatives
Tyrosine / metabolism
Tyrosine / pharmacology*

Substances

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

Associated data

PDB/1K7L
PDB/1KQQ