5C4O

Identification of a Novel Allosteric Binding Site for RORgt Inhibitors

5C4O の概要

• エントリーDOI: 10.2210/pdb5c4o/pdb
• 関連するPDBエントリー: 5C4S 5C4T 5C4U
• 分子名称: Nuclear receptor ROR-gamma, 4-{1-[2-chloro-6-(trifluoromethyl)benzoyl]-1H-indazol-3-yl}benzoic acid, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: allosteric, inhibitor, transcription-transcription inhibitor complex, transcription/transcription inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus : P51449
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29093.90

構造登録者

Parthasarathy, G.,Soisson, S. (登録日: 2015-06-18, 公開日: 2015-12-16, 最終更新日: 2024-03-06)

主引用文献

Scheepstra, M.,Leysen, S.,van Almen, G.C.,Miller, J.R.,Piesvaux, J.,Kutilek, V.,van Eenennaam, H.,Zhang, H.,Barr, K.,Nagpal, S.,Soisson, S.M.,Kornienko, M.,Wiley, K.,Elsen, N.,Sharma, S.,Correll, C.C.,Trotter, B.W.,van der Stelt, M.,Oubrie, A.,Ottmann, C.,Parthasarathy, G.,Brunsveld, L.
Identification of an allosteric binding site for ROR gamma t inhibition.
Nat Commun, 6:8833-8833, 2015

PubMed 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.

PubMed: 26640126
DOI: 10.1038/ncomms9833

実験手法

X-RAY DIFFRACTION (2.24 Å)