6TLT

ROR(gamma)t ligand binding domain in complex with desmosterol and allosteric ligand Glenmark

6TLT の概要

• エントリーDOI: 10.2210/pdb6tlt/pdb
• 分子名称: Nuclear receptor ROR-gamma, 4-[1-[2,6-bis(chloranyl)phenyl]carbonyl-5-methyl-thieno[3,2-c]pyrazol-3-yl]benzoic acid, desmosterol, ... (5 entities in total)
• 機能のキーワード: nuclear receptor, allosteric, inverse agonist, inhibitor, gene regulation
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 31422.19

構造登録者

de Vries, R.M.J.M.,Meijer, F.A.,Brunsveld, L. (登録日: 2019-12-03, 公開日: 2020-12-16, 最終更新日: 2024-01-24)

主引用文献

de Vries, R.M.J.M.,Meijer, F.A.,Doveston, R.G.,Leijten-van de Gevel, I.A.,Brunsveld, L.
Cooperativity between the orthosteric and allosteric ligand binding sites of ROR gamma t.
Proc.Natl.Acad.Sci.USA, 118:-, 2021

PubMed Abstract: Cooperative ligand binding is an important phenomenon in biological systems where ligand binding influences the binding of another ligand at an alternative site of the protein via an intramolecular network of interactions. The underlying mechanisms behind cooperative binding remain poorly understood, primarily due to the lack of structural data of these ternary complexes. Using time-resolved fluorescence resonance energy transfer (TR-FRET) studies, we show that cooperative ligand binding occurs for RORγt, a nuclear receptor associated with the pathogenesis of autoimmune diseases. To provide the crucial structural insights, we solved 12 crystal structures of RORγt simultaneously bound to various orthosteric and allosteric ligands. The presence of the orthosteric ligand induces a clamping motion of the allosteric pocket via helices 4 to 5. Additional molecular dynamics simulations revealed the unusual mechanism behind this clamping motion, with Ala355 shifting between helix 4 and 5. The orthosteric RORγt agonists regulate the conformation of Ala355, thereby stabilizing the conformation of the allosteric pocket and cooperatively enhancing the affinity of the allosteric inverse agonists.

PubMed: 33536342
DOI: 10.1073/pnas.2021287118

実験手法

X-RAY DIFFRACTION (2.11 Å)