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Submitted on April 26, 2006
Accepted on October 13, 2006
-cofactor interactions
Duke University Medical Center, Durham, NC 27710
* To whom correspondence should be addressed. E-mail: donald.mcdonnell{at}duke.edu.
Estrogen receptor-related receptor alpha (ERR
) is an orphan nuclear receptor that does not appear to require a classical small molecule ligand to facilitate its interaction with coactivators and/or hormone response elements within target genes. Instead, the apo-receptor is capable of interacting in a constitutive manner with coactivators that stimulate transcription by acting as "protein ligands". We have screened combinatorial phage libraries for peptides that selectively interact with ERR to probe the architecture of the ERR-coactivator pocket. In this manner, we have uncovered a fundamental difference in the mechanism by which this receptor interacts with PGC-1 (peroxisome proliferator-activated receptor 
(PPAR) coactivator 1-alpha) as compared with members of the SRC (steroid receptor coactivator) subfamily of coactivators. Our findings suggest that it may be possible to develop ERR ligands that exhibit different pharmacological activities as a consequence of their ability to differentially regulate coactivator recruitment. In addition, these findings have implications beyond ERR as they suggest that subtle alterations in the structure of the AF-2 pocket within any nuclear receptor may enable differential recruitment of coactivators; an observation of notable pharmaceutical importance.
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SRC
NURSA Molecule Pages Link:
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