| Structural highlights
Function
[RORG_HUMAN] Possible nuclear receptor for hydroxycholesterols, the binding of which strongly promotes coactivators recruitment. Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes. Involved in lineage specification of uncommitted CD4(+) T-helper cells into Th17 cells. Regulate the expression of several components of the circadian clock.
Publication Abstract from PubMed
RORgammat 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 RORgammat. Co-crystallization of the ligand binding domain (LBD) of RORgammat 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 RORgammat 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. RORgammat function is thus antagonized in a manner molecularly distinct from that of previously described orthosteric RORgammat ligands. This brings forward an approach to target RORgammat 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.
Identification of an allosteric binding site for RORgammat inhibition.,Scheepstra M, Leysen S, van Almen GC, Miller JR, Piesvaux J, Kutilek V, van Eenennaam H, Zhang H, Barr K, Nagpal S, Soisson SM, Kornienko M, Wiley K, Elsen N, Sharma S, Correll CC, Trotter BW, van der Stelt M, Oubrie A, Ottmann C, Parthasarathy G, Brunsveld L Nat Commun. 2015 Dec 7;6:8833. doi: 10.1038/ncomms9833. PMID:26640126[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Scheepstra M, Leysen S, van Almen GC, Miller JR, Piesvaux J, Kutilek V, van Eenennaam H, Zhang H, Barr K, Nagpal S, Soisson SM, Kornienko M, Wiley K, Elsen N, Sharma S, Correll CC, Trotter BW, van der Stelt M, Oubrie A, Ottmann C, Parthasarathy G, Brunsveld L. Identification of an allosteric binding site for RORgammat inhibition. Nat Commun. 2015 Dec 7;6:8833. doi: 10.1038/ncomms9833. PMID:26640126 doi:http://dx.doi.org/10.1038/ncomms9833
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