Identification of an allosteric binding site for ROR?t inhibition.

ABSTRACT: ROR?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?t. Co-crystallization of the ligand binding domain (LBD) of ROR?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?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?t function is thus antagonized in a manner molecularly distinct from that of previously described orthosteric ROR?t ligands. This brings forward an approach to target ROR?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.

SUBMITTER: Scheepstra M 

PROVIDER: S-EPMC4686831 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature