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

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

Research output: Contribution to journalArticle

449 Citations (Scopus)

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 corepressors 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-α 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 α-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.

Original languageEnglish (US)
Pages (from-to)813-817
Number of pages5
JournalNature
Volume415
Issue number6873
StatePublished - Feb 14 2002

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Co-Repressor Proteins
Peroxisome Proliferator-Activated Receptors
Furylfuramide
Cytoplasmic and Nuclear Receptors
Nuclear Receptor Co-Repressor 2
Thyroid Hormone Resistance Syndrome
Acute Promyelocytic Leukemia
Histone Deacetylases
Mutagenesis
Chromatin
Ligands
Genes

ASJC Scopus subject areas

  • General

Cite this

Xu, H. E., Stanley, T. B., Montana, V. G., Lambert, M. H., Shearer, B. G., Cobb, J. E., ... Stimmel, J. B. (2002). Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARα. Nature, 415(6873), 813-817.

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

In: Nature, Vol. 415, No. 6873, 14.02.2002, p. 813-817.

Research output: Contribution to journalArticle

Xu, HE, Stanley, TB, Montana, VG, Lambert, MH, Shearer, BG, Cobb, JE, McKee, DD, Galardi, CM, Plunket, KD, Nolte, RT, Parks, DJ, Moore, JT, Kliewer, SA, Willson, TM & Stimmel, JB 2002, 'Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARα', Nature, vol. 415, no. 6873, pp. 813-817.
Xu HE, Stanley TB, Montana VG, Lambert MH, Shearer BG, Cobb JE et al. Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARα. Nature. 2002 Feb 14;415(6873):813-817.
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. / Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARα. In: Nature. 2002 ; Vol. 415, No. 6873. pp. 813-817.
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N2 - 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 corepressors 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-α 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 α-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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