6G05

RORGT (264-518;C455S) IN COMPLEX WITH INVERSE AGONIST "CPD-2" AND RIP140 PEPTIDE AT 1.90A

6G05 の概要

• エントリーDOI: 10.2210/pdb6g05/pdb
• 関連するPDBエントリー: 6FZU
• 分子名称: Nuclear receptor ROR-gamma, Nuclear receptor-interacting protein 1, 2-(4-ethylsulfonylphenyl)-~{N}-[4-phenyl-5-(phenylcarbonyl)-1,3-thiazol-2-yl]ethanamide, ... (4 entities in total)
• 機能のキーワード: fbs, nuclear hormone receptor, ligand-binding domain, inverse agonist, signaling protein, transcription
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 65099.05

構造登録者

Kallen, J. (登録日: 2018-03-16, 公開日: 2018-07-18, 最終更新日: 2024-01-17)

主引用文献

Carcache, D.A.,Vulpetti, A.,Kallen, J.,Mattes, H.,Orain, D.,Stringer, R.,Vangrevelinghe, E.,Wolf, R.M.,Kaupmann, K.,Ottl, J.,Dawson, J.,Cooke, N.G.,Hoegenauer, K.,Billich, A.,Wagner, J.,Guntermann, C.,Hintermann, S.
Optimizing a Weakly Binding Fragment into a Potent ROR gamma t Inverse Agonist with Efficacy in an in Vivo Inflammation Model.
J. Med. Chem., 61:6724-6735, 2018

PubMed Abstract: The transcription factor RORγt is an attractive drug-target due to its role in the differentiation of IL-17 producing Th17 cells that play a critical role in the etiopathology of several autoimmune diseases. Identification of starting points for RORγt inverse agonists with good properties has been a challenge. We report the identification of a fragment hit and its conversion into a potent inverse agonist through fragment optimization, growing and merging efforts. Further analysis of the binding mode revealed that inverse agonism was achieved by an unusual mechanism. In contrast to other reported inverse agonists, there is no direct interaction or displacement of helix 12 observed in the crystal structure. Nevertheless, compound 9 proved to be efficacious in a delayed-type hypersensitivity (DTH) inflammation model in rats.

PubMed: 29990434
DOI: 10.1021/acs.jmedchem.8b00529

実験手法

X-RAY DIFFRACTION (1.9 Å)