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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
26
|
| pubmed:dateCreated |
1998-7-23
|
| pubmed:abstractText |
Retinoids, such as the naturally occurring all-trans-retinoic acid (atRA) and synthetic ligand CD367 modulate ligand-dependent transcription through retinoic acid receptors (RARs). Retinoid binding to RAR is believed to trigger structural transitions in the ligand-binding domain (LBD), leading to helix H1 and helix H12 repositioning and coactivator recruitment and corepressor release. Here, we carried out a detailed mutagenesis analysis of the H11-H12 loop (designated the L box) to study its contribution to hRARalpha activation process. Point mutations that reduced transactivation by atRA also reduced atRA-induced transrepression of AP1 transcription, correlating ligand-induced activation and repression. However, a correlation was not observed with these mutations when tested with another ligand CD367, a synthetic agonist with binding properties identical to those of atRA. Transcription was strongly inhibited in the presence of CD367 for some mutants, thus leading to an inverse agonist activity of this ligand. None of these mutations significantly altered binding affinity for either ligand, indicating that altered transcription was not caused by altered ligand binding by these mutations. Although simple correlations with transcriptional activities were not found, these mutations were also characterized by altered ligand-induced structural transitions, which were distinct for the atRA-hRARalpha or CD367-hRARalpha complexes. These results indicate that amino acids in the L box are involved in specifying trans-repressive and trans-activating properties of the hRARalpha, and support the notion that different agonists induce distinct conformations in the LBD of the receptor.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Adaptor Proteins, Signal Transducing,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Ligands,
http://linkedlifedata.com/resource/pubmed/chemical/NCOR2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Receptor Co-Repressor 2,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Retinoic Acid,
http://linkedlifedata.com/resource/pubmed/chemical/Repressor Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Retinoids,
http://linkedlifedata.com/resource/pubmed/chemical/Trans-Activators,
http://linkedlifedata.com/resource/pubmed/chemical/nuclear receptor interacting...,
http://linkedlifedata.com/resource/pubmed/chemical/retinoic acid receptor alpha
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Jun
|
| pubmed:issn |
0006-2960
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
30
|
| pubmed:volume |
37
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
9240-9
|
| pubmed:dateRevised |
2009-11-19
|
| pubmed:meshHeading |
pubmed-meshheading:9649304-Adaptor Proteins, Signal Transducing,
pubmed-meshheading:9649304-Amino Acid Sequence,
pubmed-meshheading:9649304-Binding, Competitive,
pubmed-meshheading:9649304-DNA-Binding Proteins,
pubmed-meshheading:9649304-Humans,
pubmed-meshheading:9649304-Ligands,
pubmed-meshheading:9649304-Models, Molecular,
pubmed-meshheading:9649304-Molecular Sequence Data,
pubmed-meshheading:9649304-Mutagenesis, Insertional,
pubmed-meshheading:9649304-Nuclear Proteins,
pubmed-meshheading:9649304-Nuclear Receptor Co-Repressor 2,
pubmed-meshheading:9649304-Point Mutation,
pubmed-meshheading:9649304-Protein Structure, Secondary,
pubmed-meshheading:9649304-Protein Structure, Tertiary,
pubmed-meshheading:9649304-Receptors, Retinoic Acid,
pubmed-meshheading:9649304-Repressor Proteins,
pubmed-meshheading:9649304-Retinoids,
pubmed-meshheading:9649304-Sequence Deletion,
pubmed-meshheading:9649304-Trans-Activators
|
| pubmed:year |
1998
|
| pubmed:articleTitle |
H11-H12 loop retinoic acid receptor mutants exhibit distinct trans-activating and trans-repressing activities in the presence of natural or synthetic retinoids.
|
| pubmed:affiliation |
INSERM U 459, Laboratoire de Biochimie Structurale, Faculté de Médecine Henri Warembourg 1, Lille, France. p.lefebvre@lille.inserm.fr
|
| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
|