Identification of an allosteric binding site for RORγt inhibition

ROR gamma t is critical for the differentiation and proliferation of Th17 cells associated with several chronic autoimmune diseases. We report the discovery of a novel allosteric binding site on the nuclear receptor ROR gamma t. Co-crystallization of the ligand binding domain (LBD) of ROR gamma t with a series of small-molecule antagonists demonstrates occupancy of a previously unreported allosteric binding pocket. Binding at this non-canonical site induces an unprecedented conformational reorientation of helix 12 in the ROR gamma t LBD, which blocks cofactor binding. The functional consequence of this allosteric ligand-mediated conformation is inhibition of function as evidenced by both biochemical and cellular studies. ROR gamma t function is thus antagonized in a manner molecularly distinct from that of previously described orthosteric ROR gamma t ligands. This brings forward an approach to target ROR gamma t for the treatment of Th17-mediated autoimmune diseases. The elucidation of an unprecedented modality of pharmacological antagonism establishes a mechanism for modulation of nuclear receptors.