Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARalpha.
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.
Xu
H Eric
HE
Nuclear Receptor Discovery Research, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. ex11957@gsk.com
Stanley
Thomas B
TB
Montana
Valerie G
VG
Lambert
Millard H
MH
Shearer
Barry G
BG
Cobb
Jeffery E
JE
McKee
David D
DD
Galardi
Cristin M
CM
Plunket
Kelli D
KD
Nolte
Robert T
RT
Parks
Derek J
DJ
Moore
John T
JT
Kliewer
Steven A
SA
Willson
Timothy M
TM
Stimmel
Julie B
JB
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D056985:Nuclear Receptor Co-Repressor 2; D010080:Oxazoles / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry* / Q000378:metabolism*; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*
D004268:DNA-Binding Proteins; C442829:GW 409544; C449302:GW 6471; D008024:Ligands; C539130:NCOR2 protein, human; D056985:Nuclear Receptor Co-Repressor 2; D010080:Oxazoles; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D014157:Transcription Factors; D014443:Tyrosine