5X8X

Crystal Structure of the mutant Human ROR gamma Ligand Binding Domain With Compound A.

5X8X の概要

• エントリーDOI: 10.2210/pdb5x8x/pdb
• 関連するPDBエントリー: 5X8Q 5X8S 5X8U 5X8W
• 分子名称: Nuclear receptor ROR-gamma, Nuclear receptor corepressor 2, (3R,4R)-4-[4-cyclopropyl-5-[3-(2-methylpropyl)cyclobutyl]-1,2,4-triazol-3-yl]-N-(2,4-dimethylphenyl)-1-ethanoyl-pyrrolidine-3-carboxamide, ... (4 entities in total)
• 機能のキーワード: inhibitor, ternary complex, nuclear receptor, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 131327.77

構造登録者

Noguchi, M.,Nomura, A.,Murase, K.,Doi, S.,Yamaguchi, K.,Adachi, T. (登録日: 2017-03-03, 公開日: 2017-06-07, 最終更新日: 2023-11-22)

主引用文献

Noguchi, M.,Nomura, A.,Murase, K.,Doi, S.,Yamaguchi, K.,Hirata, K.,Shiozaki, M.,Hirashima, S.,Kotoku, M.,Yamaguchi, T.,Katsuda, Y.,Steensma, R.,Li, X.,Tao, H.,Tse, B.,Fenn, M.,Babine, R.,Bradley, E.,Crowe, P.,Thacher, S.,Adachi, T.,Kamada, M.
Ternary complex of human ROR gamma ligand-binding domain, inverse agonist and SMRT peptide shows a unique mechanism of corepressor recruitment
Genes Cells, 22:535-551, 2017

PubMed Abstract: Retinoid-related orphan receptor gamma (RORγ) directly controls the differentiation of Th17 cell and the production of interleukin-17, which plays an integral role in autoimmune diseases. To obtain insight into RORγ, we have determined the first crystal structure of a ternary complex containing RORγ ligand-binding domain (LBD) bound with a novel synthetic inhibitor and a repressor peptide, 22-mer peptide from silencing mediator of retinoic acid and thyroid hormone receptor (SMRT). Comparison of a binary complex of nonliganded (apo) RORγ-LBD with a nuclear receptor co-activator (NCoA-1) peptide has shown that our inhibitor displays a unique mechanism different from those caused by natural inhibitor, ursolic acid (UA). The compound unprecedentedly induces indirect disruption of a hydrogen bond between His479 on helix 11 (H11) and Tyr502 on H12, which is crucial for active conformation. This crystallographic study will allow us to develop novel synthetic compounds for autoimmune disease therapy.

PubMed: 28493531
DOI: 10.1111/gtc.12494

実験手法

X-RAY DIFFRACTION (2.6 Å)