6SAL

ROR(gamma)t ligand binding domain in complex with allosteric ligand FM26

6SAL の概要

• エントリーDOI: 10.2210/pdb6sal/pdb
• 分子名称: Nuclear receptor ROR-gamma, 4-[(~{E})-[3-[2-chloranyl-6-(trifluoromethyl)phenyl]-5-(1~{H}-pyrrol-3-yl)-1,2-oxazol-4-yl]methylideneamino]benzoic acid (3 entities in total)
• 機能のキーワード: nuclear receptor, allosteric, inverse agonist, inhibitor, gene regulation
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 28802.63

構造登録者

de Vries, R.M.J.M.,Meijer, F.A.,Doveston, R.G.,Brunsveld, L. (登録日: 2019-07-17, 公開日: 2019-12-25, 最終更新日: 2024-01-24)

主引用文献

Meijer, F.A.,Doveston, R.G.,de Vries, R.M.J.M.,Vos, G.M.,Vos, A.A.A.,Leysen, S.,Scheepstra, M.,Ottmann, C.,Milroy, L.G.,Brunsveld, L.
Ligand-Based Design of Allosteric Retinoic Acid Receptor-Related Orphan Receptor gamma t (ROR gamma t) Inverse Agonists.
J.Med.Chem., 63:241-259, 2020

PubMed Abstract: Retinoic acid receptor-related orphan receptor γt (RORγt) is a nuclear receptor associated with the pathogenesis of autoimmune diseases. Allosteric inhibition of RORγt is conceptually new, unique for this specific nuclear receptor, and offers advantages over traditional orthosteric inhibition. Here, we report a highly efficient in silico-guided approach that led to the discovery of novel allosteric RORγt inverse agonists with a distinct isoxazole chemotype. The the most potent compound, (), displayed submicromolar inhibition in a coactivator recruitment assay and effectively reduced IL-17a mRNA production in EL4 cells, a marker of RORγt activity. The projected allosteric mode of action of was confirmed by biochemical experiments and cocrystallization with the RORγt ligand binding domain. The isoxazole compounds have promising pharmacokinetic properties comparable to other allosteric ligands but with a more diverse chemotype. The efficient ligand-based design approach adopted demonstrates its versatility in generating chemical diversity for allosteric targeting of RORγt.

PubMed: 31821760
DOI: 10.1021/acs.jmedchem.9b01372

実験手法

X-RAY DIFFRACTION (1.61 Å)