1KKQ

Crystal structure of the human PPAR-alpha ligand-binding domain in complex with an antagonist GW6471 and a SMRT corepressor motif

Summary for 1KKQ

• Entry DOI: 10.2210/pdb1kkq/pdb
• Related: 1k74 1k7L
• Descriptor: PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR, NUCLEAR RECEPTOR CO-REPRESSOR 2, N-((2S)-2-({(1Z)-1-METHYL-3-OXO-3-[4-(TRIFLUOROMETHYL) PHENYL]PROP-1-ENYL}AMINO)-3-{4-[2-(5-METHYL-2-PHENYL-1,3-OXAZOL-4-YL)ETHOXY]PHENYL}PROPYL)PROPANAMIDE, ... (4 entities in total)
• Functional Keywords: nuclear corepressor nuclear hormone receptors antagonist, transcription
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: Q07869 Q9Y618
• Total number of polymer chains: 8
• Total formula weight: 133211.69

Authors

Xu, H.E.,Stanley, T.B.,Montana, V.G.,Lambert, M.H.,Shearer, B.G.,Cobb, J.E.,McKee, D.D.,Galardi, C.M.,Nolte, R.T.,Parks, D.J. (deposition date: 2001-12-10, release date: 2002-02-20, Last modification date: 2023-08-16)

Primary citation

Xu, H.E.,Stanley, T.B.,Montana, V.G.,Lambert, M.H.,Shearer, B.G.,Cobb, J.E.,McKee, D.D.,Galardi, C.M.,Plunket, K.D.,Nolte, R.T.,Parks, D.J.,Moore, J.T.,Kliewer, S.A.,Willson, T.M.,Stimmel, J.B.
Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARalpha.
Nature, 415:813-817, 2002

PubMed 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.

PubMed: 11845213

Experimental method

X-RAY DIFFRACTION (3 Å)