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Identification of an allosteric binding site for RORγt inhibition

Author

Listed:
  • Marcel Scheepstra

    (Laboratory of Chemical Biology, Eindhoven University of Technology)

  • Seppe Leysen

    (Laboratory of Chemical Biology, Eindhoven University of Technology)

  • Geert C. van Almen

    (Laboratory of Chemical Biology, Eindhoven University of Technology)

  • J. Richard Miller

    (Merck Research Laboratories)

  • Jennifer Piesvaux

    (Merck Research Laboratories)

  • Victoria Kutilek

    (Merck Research Laboratories)

  • Hans van Eenennaam

    (Merck Research Laboratories
    Present address: BioNovion B.V., Pivot Park, Molenweg 79, 5349 AC Oss, The Netherlands)

  • Hongjun Zhang

    (Merck Research Laboratories)

  • Kenneth Barr

    (Merck Research Laboratories
    Present address: FORMA Therapeutics, Inc., 500 Arsenal Street, Suite 500, Watertown, Massachusetts 02472, USA)

  • Sunil Nagpal

    (Merck Research Laboratories
    Present address: Research Immunology, Janssen Research, 1400 McKean Road, Spring House, Pennsylvania 19477, USA)

  • Stephen M. Soisson

    (Merck Research Laboratories)

  • Maria Kornienko

    (Merck Research Laboratories)

  • Kristen Wiley

    (Merck Research Laboratories)

  • Nathaniel Elsen

    (Merck Research Laboratories
    Present address: AbbVie Inc., Target Enabling Science and Technology, 1 North Waukegan Road, North Chicago, Illinois 60064, USA)

  • Sujata Sharma

    (Merck Research Laboratories)

  • Craig C. Correll

    (Merck Research Laboratories)

  • B. Wesley Trotter

    (Merck Research Laboratories)

  • Mario van der Stelt

    (Merck Research Laboratories
    Present address: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden university, Einsteinweg 55, 2333CC Leiden, The Netherlands)

  • Arthur Oubrie

    (Merck Research Laboratories
    Present address: Lead Pharma, Novio Tech Campus, Industrieterrein Winkelsteeg, Transistorweg 5, 6534 AT Nijmegen, The Netherlands)

  • Christian Ottmann

    (Laboratory of Chemical Biology, Eindhoven University of Technology)

  • Gopal Parthasarathy

    (Merck Research Laboratories)

  • Luc Brunsveld

    (Laboratory of Chemical Biology, Eindhoven University of Technology)

Abstract

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

Suggested Citation

  • Marcel Scheepstra & Seppe Leysen & Geert C. van Almen & J. Richard Miller & Jennifer Piesvaux & Victoria Kutilek & Hans van Eenennaam & Hongjun Zhang & Kenneth Barr & Sunil Nagpal & Stephen M. Soisson, 2015. "Identification of an allosteric binding site for RORγt inhibition," Nature Communications, Nature, vol. 6(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9833
    DOI: 10.1038/ncomms9833
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