title: Identification of an allosteric binding site for RORγt inhibition.
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.
authors.affiliation: Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute of Complex Molecular Systems, Eindhoven University of Technology, PO Box 513, Eindhoven 5600MB, The Netherlands.
authors.forename: Marcel
authors.initials: M
authors.lastname: Scheepstra
authors.affiliation: Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute of Complex Molecular Systems, Eindhoven University of Technology, PO Box 513, Eindhoven 5600MB, The Netherlands.
authors.forename: Seppe
authors.initials: S
authors.lastname: Leysen
authors.affiliation: Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute of Complex Molecular Systems, Eindhoven University of Technology, PO Box 513, Eindhoven 5600MB, The Netherlands.
authors.forename: Geert C
authors.initials: GC
authors.lastname: van Almen
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
authors.forename: J Richard
authors.initials: JR
authors.lastname: Miller
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Piesvaux
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Kutilek
authors.affiliation: Merck Research Laboratories, Molenstraat 110, Oss 5342 CC, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: van Eenennaam
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Barr
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
authors.forename: Sunil
authors.initials: S
authors.lastname: Nagpal
authors.affiliation: Merck Research Laboratories, 770 Sumneytown Pike, West Point, Pennsylvania 19486, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Soisson
authors.affiliation: Merck Research Laboratories, 503 Louise Lane, North Wales, Pennsylvania 19454, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Kornienko
authors.affiliation: Merck Research Laboratories, 503 Louise Lane, North Wales, Pennsylvania 19454, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Wiley
authors.affiliation: Merck Research Laboratories, 503 Louise Lane, North Wales, Pennsylvania 19454, USA.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Elsen
authors.affiliation: Merck Research Laboratories, 503 Louise Lane, North Wales, Pennsylvania 19454, USA.
authors.forename: Sujata
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
authors.forename: Craig C
authors.initials: CC
authors.lastname: Correll
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
authors.forename: B Wesley
authors.initials: BW
authors.lastname: Trotter
authors.affiliation: Merck Research Laboratories, Molenstraat 110, Oss 5342 CC, The Netherlands.
authors.forename: Mario
authors.initials: M
authors.lastname: van der Stelt
authors.affiliation: Merck Research Laboratories, Molenstraat 110, Oss 5342 CC, The Netherlands.
authors.forename: Arthur
authors.initials: A
authors.lastname: Oubrie
authors.affiliation: Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute of Complex Molecular Systems, Eindhoven University of Technology, PO Box 513, Eindhoven 5600MB, The Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Ottmann
authors.affiliation: Merck Research Laboratories, 770 Sumneytown Pike, West Point, Pennsylvania 19486, USA.
authors.forename: Gopal
authors.initials: G
authors.lastname: Parthasarathy
authors.affiliation: Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute of Complex Molecular Systems, Eindhoven University of Technology, PO Box 513, Eindhoven 5600MB, The Netherlands.
authors.forename: Luc
authors.initials: L
authors.lastname: Brunsveld
mesh_terms: D000495:Allosteric Site; D000818:Animals; D002454:Cell Differentiation; D006801:Humans; D020381:Interleukin-17 / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D058504:Th17 Cells / Q000737:chemistry / Q000378:metabolism
chemical_list: D020381:Interleukin-17; D008024:Ligands; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; C539901:Rorc protein, mouse