3B0W

Crystal structure of the orphan nuclear receptor ROR(gamma)t ligand-binding domain in complex with digoxin

3B0W の概要

• エントリーDOI: 10.2210/pdb3b0w/pdb
• 分子名称: Nuclear receptor ROR-gamma, DIGOXIN (3 entities in total)
• 機能のキーワード: three-layered alpha helical sandwich, orphan nuclear receptor, ligand-binding domain, antagonist, transcription-inhibitor complex, 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: 2
• 化学式量合計: 58177.52

構造登録者

Fujita-Sato, S.,Ito, S.,Isobe, T.,Ohyama, T.,Wakabayashi, K.,Morishita, K.,Ando, O.,Isono, F. (登録日: 2011-06-17, 公開日: 2011-07-06, 最終更新日: 2023-11-01)

主引用文献

Fujita-Sato, S.,Ito, S.,Isobe, T.,Ohyama, T.,Wakabayashi, K.,Morishita, K.,Ando, O.,Isono, F.
Structural Basis of Digoxin That Antagonizes ROR{gamma}t Receptor Activity and Suppresses Th17 Cell Differentiation and Interleukin (IL)-17 Production
J.Biol.Chem., 286:31409-31417, 2011

PubMed Abstract: The retinoic acid-related orphan nuclear receptor γt (RORγt)/RORγ2 is well known as a master regulator of interleukin 17 (IL-17)-producing helper T (Th17) cell development. To develop a therapeutic agent against Th17-mediated autoimmune diseases, we screened chemical compounds and successfully found that digoxin inhibited IL-17 production. Further studies revealed that digoxin bound to the ligand binding domain of RORγt and suppressed Th17 differentiation without affecting Th1 differentiation. To better understand the structural basis for the inhibitory activity of digoxin, we determined the crystal structure of the RORγt ligand-binding domain in complex with digoxin at 2.2 Å resolution. The structure reveals that digoxin binds to the ligand-binding pocket protruding between helices H3 and H11 from the pocket. In addition, digoxin disrupts the key interaction important for the agonistic activity, resulting in preventing the positioning of helix H12 in the active conformation, thus antagonizing coactivator interaction. Functional studies demonstrated that digoxin inhibited RORγt activity and decreased IL-17 production but not RORα activity. Digoxin inhibited IL-17 production in CD4(+) T cells from experimental autoimmune encephalomyelitis mice. Our data indicates that RORγt is a promising therapeutic target for Th17-derived autoimmune diseases and our structural data will help to design novel RORγt antagonists.

PubMed: 21733845
DOI: 10.1074/jbc.M111.254003

実験手法

X-RAY DIFFRACTION (2.2 Å)