6NWT

RORgamma Ligand Binding Domain

6NWT の概要

• エントリーDOI: 10.2210/pdb6nwt/pdb
• 分子名称: Nuclear receptor ROR-gamma, 1,1,1,3,3,3-hexafluoro-2-[2-fluoro-4'-({4-[(pyridin-4-yl)methyl]piperazin-1-yl}methyl)[1,1'-biphenyl]-4-yl]propan-2-ol (3 entities in total)
• 機能のキーワード: orphan nuclear receptor, synthetic modulator, chemical probe, nuclear protein
• 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: 58012.91

構造登録者

Strutzenberg, T.S.,Park, H.,Griffin, P.R. (登録日: 2019-02-07, 公開日: 2019-07-10, 最終更新日: 2023-10-11)

主引用文献

Strutzenberg, T.S.,Garcia-Ordonez, R.D.,Novick, S.J.,Park, H.,Chang, M.R.,Doebellin, C.,He, Y.,Patouret, R.,Kamenecka, T.M.,Griffin, P.R.
HDX-MS reveals structural determinants for ROR gamma hyperactivation by synthetic agonists.
Elife, 8:-, 2019

PubMed Abstract: Members of the nuclear receptor (NR) superfamily regulate both physiological and pathophysiological processes ranging from development and metabolism to inflammation and cancer. Synthetic small molecules targeting NRs are often deployed as therapeutics to correct aberrant NR signaling or as chemical probes to explore the role of the receptor in physiology. Nearly half of NRs do not have specific cognate ligands (termed orphan NRs) and it's unclear if they possess ligand dependent activities. Here we demonstrate that ligand-dependent action of the orphan RORγ can be defined by selectively disrupting putative endogenous-but not synthetic-ligand binding. Furthermore, the characterization of a library of RORγ modulators reveals that structural dynamics of the receptor assessed by HDX-MS correlate with activity in biochemical and cell-based assays. These findings, corroborated with X-ray co-crystallography and site-directed mutagenesis, collectively reveal the structural determinants of RORγ activation, which is critical for designing RORγ agonists for cancer immunotherapy.

PubMed: 31172947
DOI: 10.7554/eLife.47172

実験手法

X-RAY DIFFRACTION (2.35 Å)