期刊
NATURE COMMUNICATIONS
卷 6, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms9833
关键词
-
资金
- Netherlands Organization for Scientific Research via Gravity program [024.001.035]
- ECHO via Marie Curie Action [711011017, PIAPP-GA-2011-28641814-3-3Stabs]
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.
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