Identification of an allosteric binding site for RORγt inhibition

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 () and Luc Brunsveld ()
Additional contact information
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
Hongjun Zhang: Merck Research Laboratories
Kenneth Barr: Merck Research Laboratories
Sunil Nagpal: Merck Research Laboratories
Stephen M. Soisson: Merck Research Laboratories
Maria Kornienko: Merck Research Laboratories
Kristen Wiley: Merck Research Laboratories
Nathaniel Elsen: Merck Research Laboratories
Sujata Sharma: Merck Research Laboratories
Craig C. Correll: Merck Research Laboratories
B. Wesley Trotter: Merck Research Laboratories
Mario van der Stelt: Merck Research Laboratories
Arthur Oubrie: Merck Research Laboratories
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

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: 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.

Date: 2015
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/ncomms9833 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9833

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms9833

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().