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 and Julie B. Stimmel
Additional contact information
H. Eric Xu: Nuclear Receptor Discovery Research, GlaxoSmithKline
Thomas B. Stanley: Nuclear Receptor Discovery Research, GlaxoSmithKline
Valerie G. Montana: Nuclear Receptor Discovery Research, GlaxoSmithKline
Millard H. Lambert: Nuclear Receptor Discovery Research, GlaxoSmithKline
Barry G. Shearer: Nuclear Receptor Discovery Research, GlaxoSmithKline
Jeffery E. Cobb: Nuclear Receptor Discovery Research, GlaxoSmithKline
David D. McKee: Nuclear Receptor Discovery Research, GlaxoSmithKline
Cristin M. Galardi: Nuclear Receptor Discovery Research, GlaxoSmithKline
Kelli D. Plunket: Nuclear Receptor Discovery Research, GlaxoSmithKline
Robert T. Nolte: Nuclear Receptor Discovery Research, GlaxoSmithKline
Derek J. Parks: Nuclear Receptor Discovery Research, GlaxoSmithKline
John T. Moore: Nuclear Receptor Discovery Research, GlaxoSmithKline
Steven A. Kliewer: Nuclear Receptor Discovery Research, GlaxoSmithKline
Timothy M. Willson: Nuclear Receptor Discovery Research, GlaxoSmithKline
Julie B. Stimmel: Nuclear Receptor Discovery Research, GlaxoSmithKline

Nature, 2002, vol. 415, issue 6873, 813-817

Abstract: Abstract Repression of gene transcription by nuclear receptors is mediated by interactions with co-repressor proteins such as SMRT and N-CoR1,2, which in turn recruit histone deacetylases to the chromatin3,4,5. Aberrant interactions between nuclear receptors and co-repressors contribute towards acute promyelocytic leukaemia and thyroid hormone resistance syndrome6,7,8. The binding of co-repressors to nuclear receptors occurs in the unliganded state, and can be stabilized by antagonists9. 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.

Date: 2002
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DOI: 10.1038/415813a

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