|
rdf:type |
|
|
lifeskim:mentions |
|
|
pubmed:issue |
6873
|
|
pubmed:dateCreated |
2002-2-14
|
|
pubmed:databankReference |
|
|
pubmed:abstractText |
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:language |
eng
|
|
pubmed:journal |
|
|
pubmed:citationSubset |
IM
|
|
pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/GW 409544,
http://linkedlifedata.com/resource/pubmed/chemical/Ligands,
http://linkedlifedata.com/resource/pubmed/chemical/NCOR2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Receptor Co-Repressor 2,
http://linkedlifedata.com/resource/pubmed/chemical/Oxazoles,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Cytoplasmic and Nuclear,
http://linkedlifedata.com/resource/pubmed/chemical/Repressor Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/Tyrosine
|
|
pubmed:status |
MEDLINE
|
|
pubmed:month |
Feb
|
|
pubmed:issn |
0028-0836
|
|
pubmed:author |
pubmed-author:CobbJeffery EJE,
pubmed-author:GalardiCristin MCM,
pubmed-author:KliewerSteven ASA,
pubmed-author:LambertMillard HMH,
pubmed-author:McKeeDavid DDD,
pubmed-author:MontanaValerie GVG,
pubmed-author:MooreJohn TJT,
pubmed-author:NolteRobert TRT,
pubmed-author:ParksDerek JDJ,
pubmed-author:PlunketKelli DKD,
pubmed-author:ShearerBarry GBG,
pubmed-author:StanleyThomas BTB,
pubmed-author:StimmelJulie BJB,
pubmed-author:WillsonTimothy MTM,
pubmed-author:XuH EricHE
|
|
pubmed:issnType |
Print
|
|
pubmed:day |
14
|
|
pubmed:volume |
415
|
|
pubmed:owner |
NLM
|
|
pubmed:authorsComplete |
Y
|
|
pubmed:pagination |
813-7
|
|
pubmed:dateRevised |
2009-11-19
|
|
pubmed:meshHeading |
pubmed-meshheading:11845213-Amino Acid Motifs,
pubmed-meshheading:11845213-Amino Acid Sequence,
pubmed-meshheading:11845213-Binding Sites,
pubmed-meshheading:11845213-Crystallography, X-Ray,
pubmed-meshheading:11845213-DNA-Binding Proteins,
pubmed-meshheading:11845213-Humans,
pubmed-meshheading:11845213-Inhibitory Concentration 50,
pubmed-meshheading:11845213-Ligands,
pubmed-meshheading:11845213-Models, Molecular,
pubmed-meshheading:11845213-Molecular Sequence Data,
pubmed-meshheading:11845213-Nuclear Receptor Co-Repressor 2,
pubmed-meshheading:11845213-Oxazoles,
pubmed-meshheading:11845213-Protein Binding,
pubmed-meshheading:11845213-Protein Structure, Secondary,
pubmed-meshheading:11845213-Protein Structure, Tertiary,
pubmed-meshheading:11845213-Receptors, Cytoplasmic and Nuclear,
pubmed-meshheading:11845213-Repressor Proteins,
pubmed-meshheading:11845213-Sequence Alignment,
pubmed-meshheading:11845213-Structure-Activity Relationship,
pubmed-meshheading:11845213-Transcription Factors,
pubmed-meshheading:11845213-Tyrosine
|
|
pubmed:year |
2002
|
|
pubmed:articleTitle |
Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARalpha.
|
|
pubmed:affiliation |
Nuclear Receptor Discovery Research, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. ex11957@gsk.com
|
|
pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, Non-P.H.S.
|
