Identification of an allosteric binding site for RORγt inhibition

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 sma...

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Vydáno v:	Nature communications Ročník 6; číslo 1; s. 8833
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 07.12.2015 Nature Publishing Group
Témata:	60 APPLIED LIFE SCIENCES 631/45/612/388 631/57/2272 692/699/2743/1313 692/700/565/1331 82 82/80 82/83 Allosteric Site Animals Cell Differentiation Humanities and Social Sciences Humans Interleukin-17 - chemistry Interleukin-17 - metabolism Ligands Mice multidisciplinary Nuclear Receptor Subfamily 1, Group F, Member 3 - chemistry Nuclear Receptor Subfamily 1, Group F, Member 3 - genetics Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism Protein Structure, Tertiary Science Science (multidisciplinary) Th17 Cells - chemistry Th17 Cells - metabolism
ISSN:	2041-1723, 2041-1723
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Shrnutí:	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. Upon the binding of small ligands, nuclear receptors regulate the transcription of genes that are associated with a number of disease mechanisms. Here, the authors report on a novel allosteric ligand binding site on the nuclear receptor RORγt.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 USDOE These authors contributed equally to this work. Present address: FORMA Therapeutics, Inc., 500 Arsenal Street, Suite 500, Watertown, Massachusetts 02472, USA Present address: Lead Pharma, Novio Tech Campus, Industrieterrein Winkelsteeg, Transistorweg 5, 6534 AT Nijmegen, The Netherlands Present address: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden university, Einsteinweg 55, 2333CC Leiden, The Netherlands Present address: BioNovion B.V., Pivot Park, Molenweg 79, 5349 AC Oss, The Netherlands Present address: Research Immunology, Janssen Research, 1400 McKean Road, Spring House, Pennsylvania 19477, USA Present address: AbbVie Inc., Target Enabling Science and Technology, 1 North Waukegan Road, North Chicago, Illinois 60064, USA
ISSN:	2041-1723 2041-1723
DOI:	10.1038/ncomms9833