4S14

Crystal structure of the orphan nuclear receptor RORgamma ligand-binding domain in complex with 4alpha-caboxyl, 4beta-methyl-zymosterol (4ACD8)

4S14 の概要

• エントリーDOI: 10.2210/pdb4s14/pdb
• 関連するPDBエントリー: 4S15
• 分子名称: Nuclear receptor ROR-gamma, Nuclear receptor-interacting protein 1, (3beta,4alpha,5beta,14beta)-3-hydroxy-4-methylcholesta-8,24-diene-4-carboxylic acid (3 entities in total)
• 機能のキーワード: transcription factor, transcription
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Nucleus : P51449 P48552
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 31736.84

構造登録者

Huang, P.,Santori, F.R.,Littman, D.R.,Rastinejad, F. (登録日: 2015-01-07, 公開日: 2015-02-11, 最終更新日: 2024-11-06)

主引用文献

Santori, F.R.,Huang, P.,van de Pavert, S.A.,Douglass, E.F.,Leaver, D.J.,Haubrich, B.A.,Keber, R.,Lorbek, G.,Konijn, T.,Rosales, B.N.,Rozman, D.,Horvat, S.,Rahier, A.,Mebius, R.E.,Rastinejad, F.,Nes, W.D.,Littman, D.R.
Identification of Natural ROR gamma Ligands that Regulate the Development of Lymphoid Cells.
Cell Metab, 21:286-297, 2015

PubMed Abstract: Mice deficient in the nuclear hormone receptor RORγt have defective development of thymocytes, lymphoid organs, Th17 cells, and type 3 innate lymphoid cells. RORγt binds to oxysterols derived from cholesterol catabolism, but it is not clear whether these are its natural ligands. Here, we show that sterol lipids are necessary and sufficient to drive RORγt-dependent transcription. We combined overexpression, RNAi, and genetic deletion of metabolic enzymes to study RORγ-dependent transcription. Our results are consistent with the RORγt ligand(s) being a cholesterol biosynthetic intermediate (CBI) downstream of lanosterol and upstream of zymosterol. Analysis of lipids bound to RORγ identified molecules with molecular weights consistent with CBIs. Furthermore, CBIs stabilized the RORγ ligand-binding domain and induced coactivator recruitment. Genetic deletion of metabolic enzymes upstream of the RORγt-ligand(s) affected the development of lymph nodes and Th17 cells. Our data suggest that CBIs play a role in lymphocyte development potentially through regulation of RORγt.

PubMed: 25651181
DOI: 10.1016/j.cmet.2015.01.004

実験手法

X-RAY DIFFRACTION (3.542 Å)