6E3E

Structure of RORgt in complex with a novel inverse agonist.

6E3E の概要

• エントリーDOI: 10.2210/pdb6e3e/pdb
• 分子名称: Nuclear receptor ROR-gamma, SULFATE ION, (4S)-2-METHYL-2,4-PENTANEDIOL, ... (5 entities in total)
• 機能のキーワード: nuclear hormone receptor, inverse agonist, nuclear protein-agonist complex, nuclear protein/agonist
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 51853.86

構造登録者

Skene, R.J.,Hoffman, I. (登録日: 2018-07-13, 公開日: 2019-07-17, 最終更新日: 2024-03-13)

主引用文献

Yukawa, T.,Nara, Y.,Kono, M.,Sato, A.,Oda, T.,Takagi, T.,Sato, T.,Banno, Y.,Taya, N.,Imada, T.,Shiokawa, Z.,Negoro, N.,Kawamoto, T.,Koyama, R.,Uchiyama, N.,Skene, R.,Hoffman, I.,Chen, C.H.,Sang, B.,Snell, G.,Katsuyama, R.,Yamamoto, S.,Shirai, J.
Design, Synthesis, and Biological Evaluation of Retinoic Acid-Related Orphan Receptor gamma t (ROR gamma t) Agonist Structure-Based Functionality Switching Approach from In House ROR gamma t Inverse Agonist to ROR gamma t Agonist.
J.Med.Chem., 62:1167-1179, 2019

PubMed Abstract: Retinoic acid receptor-related orphan receptor γt (RORγt) agonists are expected to provide a novel class of immune-activating anticancer drugs via activation of Th17 cells and Tc17 cells. Herein, we describe a novel structure-based functionality switching approach from in house well-optimized RORγt inverse agonists to potent RORγt agonists. We succeeded in the identification of potent RORγt agonist 5 without major chemical structure change. The biochemical response was validated by molecular dynamics simulation studies that showed a helix 12 stabilization effect of RORγt agonists. These results indicate that targeting helix 12 is an attractive and novel medicinal chemistry strategy for switching existing RORγt inverse agonists to agonists.

PubMed: 30652849
DOI: 10.1021/acs.jmedchem.8b01181

実験手法

X-RAY DIFFRACTION (2.47 Å)