4WQP

Crystal structure of RORc in complex with a benzyl sulfonamide inverse agonist

4WQP の概要

• エントリーDOI: 10.2210/pdb4wqp/pdb
• 分子名称: Nuclear receptor ROR-gamma, VAL-GLU-ARG-LEU-GLN-ILE-PHE-GLN-HIS-LEU-HIS-PRO-ILE, N-[4-(4-acetylpiperazin-1-yl)benzyl]-N-(2-methylpropyl)-1-phenylmethanesulfonamide, ... (5 entities in total)
• 機能のキーワード: nuclear receptor ligand binding domain, transcription
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Nucleus : P51449
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 64419.26

構造登録者

Boenig, G.,Hymowitz, S.G. (登録日: 2014-10-22, 公開日: 2015-01-14, 最終更新日: 2023-12-27)

主引用文献

Rene, O.,Fauber, B.P.,de Leon Boenig, G.,Burton, B.,Eidenschenk, C.,Everett, C.,Gobbi, A.,Hymowitz, S.G.,Johnson, A.R.,Kiefer, J.R.,Liimatta, M.,Lockey, P.,Norman, M.,Ouyang, W.,Wallweber, H.A.,Wong, H.
Minor Structural Change to Tertiary Sulfonamide RORc Ligands Led to Opposite Mechanisms of Action.
Acs Med.Chem.Lett., 6:276-281, 2015

PubMed Abstract: A minor structural change to tertiary sulfonamide RORc ligands led to distinct mechanisms of action. Co-crystal structures of two compounds revealed mechanistically consistent protein conformational changes. Optimized phenylsulfonamides were identified as RORc agonists while benzylsulfonamides exhibited potent inverse agonist activity. Compounds behaving as agonists in our biochemical assay also gave rise to an increased production of IL-17 in human PBMCs whereas inverse agonists led to significant suppression of IL-17 under the same assay conditions. The most potent inverse agonist compound showed >180-fold selectivity over the ROR isoforms as well as all other nuclear receptors that were profiled.

PubMed: 25815138
DOI: 10.1021/ml500420y

実験手法

X-RAY DIFFRACTION (1.99 Å)