Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARalpha.
Nature
; 415(6873): 813-7, 2002 Feb 14.
Article
en En
| MEDLINE
| ID: mdl-11845213
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.
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Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Oxazoles
/
Proteínas Represoras
/
Tirosina
/
Factores de Transcripción
/
Receptores Citoplasmáticos y Nucleares
/
Proteínas de Unión al ADN
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Nature
Año:
2002
Tipo del documento:
Article
País de afiliación:
Estados Unidos