XL-MS of RORg:RORE:SRC3 Complexes

The retinoic acid receptor-related orphan receptor γ (RORγ) is a ligand-dependent transcription factor that both underpins metabolic and immune functions and provides vantage to manipulate those processes pharmacologically. Despite its importance, our understanding of the ligand-dependent activities of RORγ is far from complete and developing a detailed structural model for RORγ pharmacology could provide a path towards the development of safe and efficacious therapeutics targeting the receptor. Herein, we examine the ligand-dependent assembly of recombinant RORγ:coregulator complexes on cognate DNA response elements using structural proteomics and small angle x-ray scattering. These studies reveal that the RORγ DNA binding domain can bind multiple different sequences of DNA, and that coregulatory proteins may be able to ‘sense’ the ligand- and DNA-bound status of RORγ. Overall, the efforts described herein will illuminate important aspects of RORγ activity and drug development that could lead to more efficacious treatments targeting this important receptor.