首页|Identification of an allosteric binding site for ROR gamma t inhibition

Identification of an allosteric binding site for ROR gamma t inhibition

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  • NSTL
  • Springer Nature
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.

NUCLEAR RECEPTORINVERSE AGONISTSSTRUCTURAL BASISESTROGEN-RECEPTORPROTEINLIGANDDIFFERENTIATIONAUTOIMMUNITYMODULATORSINTERFACE

Scheepstra, Marcel、Leysen, Seppe、van Almen, Geert C.、Miller, J. Richard、Piesvaux, Jennifer、Kutilek, Victoria、van Eenennaam, Hans、Zhang, Hongjun、Barr, Kenneth、Nagpal, Sunil、Soisson, Stephen M.、Kornienko, Maria、Wiley, Kristen、Elsen, Nathaniel、Sharma, Sujata、Correll, Craig C.、Trotter, B. Wesley、van der Stelt, Mario、Oubrie, Arthur、Ottmann, Christian、Parthasarathy, Gopal、Brunsveld, Luc

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Eindhoven Univ Technol, Dept Biomed Engn, Biol Chem Lab, NL-5600 MB Eindhoven, Netherlands

Merck Res Labs, Boston, MA 02115 USA

Merck Res Labs, NL-5342 CC Oss, Netherlands

Merck Res Labs, West Point, PA 19486 USA

Merck Res Labs, N Wales, PA 19454 USA

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2015

10.1038/ncomms9833

Nature Communications

Nature Communications

AHCI
ISSN：2041-1723
年,卷(期)：2015.6(Dec.)
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