Identification of an allosteric binding site for RORγt inhibition

被引：0

作者：

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

Maria Kornienko

Kristen Wiley

Nathaniel Elsen

Sujata Sharma

Craig C. Correll

B. Wesley Trotter

Mario van der Stelt

Arthur Oubrie

Christian Ottmann

Gopal Parthasarathy

Luc Brunsveld

机构：

[1] Laboratory of Chemical Biology,Department of Biomedical Engineering and Institute of Complex Molecular Systems

[2] Eindhoven University of Technology,undefined

[3] Merck Research Laboratories,undefined

[4] Merck Research Laboratories,undefined

[5] Merck Research Laboratories,undefined

[6] Merck Research Laboratories,undefined

[7] Present address: BioNovion B.V.,undefined

[8] Pivot Park,undefined

[9] Molenweg 79,undefined

[10] 5349 AC Oss,undefined

[11] The Netherlands,undefined

[12] Present address: FORMA Therapeutics,undefined

[13] Inc.,undefined

[14] 500 Arsenal Street,undefined

[15] Suite 500,undefined

[16] Watertown,undefined

[17] Massachusetts 02472,undefined

[18] USA,undefined

[19] Present address: Research Immunology,undefined

[20] Janssen Research,undefined

[21] 1400 McKean Road,undefined

[22] Spring House,undefined

[23] Pennsylvania 19477,undefined

[24] USA,undefined

[25] Present address: AbbVie Inc.,undefined

[26] Target Enabling Science and Technology,undefined

[27] 1 North Waukegan Road,undefined

[28] North Chicago,undefined

[29] Illinois 60064,undefined

[30] USA,undefined

[31] Present address: Department of Molecular Physiology,undefined

[32] Leiden Institute of Chemistry,undefined

[33] Leiden university,undefined

[34] Einsteinweg 55,undefined

[35] 2333CC Leiden,undefined

[36] The Netherlands,undefined

[37] Present address: Lead Pharma,undefined

[38] Novio Tech Campus,undefined

[39] Industrieterrein Winkelsteeg,undefined

[40] Transistorweg 5,undefined

[41] 6534 AT Nijmegen,undefined

[42] The Netherlands,undefined

来源：

Nature Communications | / 6卷

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摘要：

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.

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