Structural determinant for inducing RORgamma specific inverse agonism triggered by a synthetic benzoxazinone ligand.

ABSTRACT:

Background

The nuclear hormone receptor RORγ regulates transcriptional genes involved in the production of the pro-inflammatory interleukin IL-17 which has been linked to autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. This transcriptional activity of RORγ is modulated through a protein-protein interaction involving the activation function 2 (AF2) helix on the ligand binding domain of RORγ and a conserved LXXLL helix motif on coactivator proteins. Our goal was to develop a RORγ specific inverse agonist that would help down regulate pro-inflammatory gene transcription by disrupting the protein protein interaction with coactivator proteins as a therapeutic agent.

Results

We identified a novel series of synthetic benzoxazinon

SUBMITTER: Marcotte DJ 

PROVIDER: S-EPMC4888278 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature