Linked Life Data

15761029

Source:http://linkedlifedata.com/resource/pubmed/id/15761029

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2005-5-25
pubmed:abstractText
We investigated the coregulator (coactivator and corepressor) interactions with the mineralocorticoid receptor (MR) that lead to activation and inhibition of the receptor in the presence of agonist and/or antagonist. Our results indicate that MR ligand binding domain (LBD) interacts strongly with only a few specific coactivator peptides in the presence of the agonist aldosterone and that these interactions are blocked by the antagonist eplerenone. We also discovered that cortisol, the preferred physiological ligand for the glucocorticoid receptor in humans, is a partial MR agonist/antagonist, providing a possible molecular explanation of the tissue-selective effects of glucocorticoids on MR. However, when we examined the coactivator and corepressor peptide interactions in the presence of cortisol, we found that MR bound with cortisol or aldosterone interacted with the same set of peptides. Thus, the partial agonism shown by cortisol is unlikely to be the result of differential interaction with known coactivators and corepressors. On the other hand, we have identified coactivator binding groove mutations that are critical for cortisol activation but not for aldosterone activation, suggesting that the two steroids induce different MR LBD conformations. In addition, we also show that cortisol becomes full agonist when S810L mutation is introduced in the LBD of MR. Interestingly, MR antagonists, such as eplerenone and progesterone, become partial agonist/antagonist of S810L but are still able to recruit LXXLL peptides to the mutant receptor. Together, these findings suggest a model to explain the MR activation by various ligands.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0888-8809
pubmed:author
pubmed:issnType
Print
pubmed:volume
19
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1460-73
pubmed:meshHeading
pubmed-meshheading:15761029-Aldosterone, pubmed-meshheading:15761029-Amino Acid Motifs, pubmed-meshheading:15761029-Amino Acid Sequence, pubmed-meshheading:15761029-Cell Line, pubmed-meshheading:15761029-Cells, Cultured, pubmed-meshheading:15761029-Dose-Response Relationship, Drug, pubmed-meshheading:15761029-Fluorescence Resonance Energy Transfer, pubmed-meshheading:15761029-Gene Expression Regulation, pubmed-meshheading:15761029-Glucocorticoids, pubmed-meshheading:15761029-Humans, pubmed-meshheading:15761029-Hydrocortisone, pubmed-meshheading:15761029-Ligands, pubmed-meshheading:15761029-Models, Biological, pubmed-meshheading:15761029-Molecular Sequence Data, pubmed-meshheading:15761029-Mutation, pubmed-meshheading:15761029-Peptides, pubmed-meshheading:15761029-Protein Binding, pubmed-meshheading:15761029-Protein Conformation, pubmed-meshheading:15761029-Protein Structure, Tertiary, pubmed-meshheading:15761029-Receptors, Mineralocorticoid, pubmed-meshheading:15761029-Sequence Homology, Amino Acid, pubmed-meshheading:15761029-Spironolactone, pubmed-meshheading:15761029-Transcription, Genetic, pubmed-meshheading:15761029-Transfection
pubmed:year
2005
pubmed:articleTitle
The ligand-dependent interaction of mineralocorticoid receptor with coactivator and corepressor peptides suggests multiple activation mechanisms.
pubmed:affiliation
St. Louis Laboratories, Biological Sciences, Pfizer Global Research & Development, Missouri 63017, USA.
pubmed:publicationType
Journal Article