6TLM

ROR(gamma)t ligand binding domain in complex with allosteric ligand compound 13 (Glenmark)

6TLM の概要

• エントリーDOI: 10.2210/pdb6tlm/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 (3 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: 30945.46

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: 2020-03-04, 最終更新日: 2024-01-24)

主引用文献

de Vries, R.M.J.M.,Doveston, R.G.,Meijer, F.A.,Brunsveld, L.
Elucidation of an Allosteric Mode of Action for a Thienopyrazole ROR gamma t Inverse Agonist.
Chemmedchem, 15:561-565, 2020

PubMed Abstract: The demand for allosteric targeting of nuclear receptors is high, but examples are limited, and structural information is scarce. The retinoic acid-related orphan receptor gamma t (RORγt) is an important transcriptional regulator for the differentiation of T helper 17 cells for which the first, and some of the most promising, examples of allosteric nuclear receptor modulation have been reported and structurally proven. In a 2015 patent, filed by the pharmaceutical company Glenmark, a new class of small molecules was reported that act as potent inverse agonists for RORγt. A compound library around the central thienopyrazole scaffold captured a clear structure-activity relationship, but the binding mechanism of this new class of RORγt modulators has not been elucidated. Using a combination of biochemical and X-ray crystallography studies, here the allosteric mechanism for the inverse agonism for the most potent compound, classified in the patent as "example 13", is reported, providing a strongly desired additional example of allosteric nuclear receptor targeting.

PubMed: 32053744
DOI: 10.1002/cmdc.202000044

実験手法

X-RAY DIFFRACTION (2.321 Å)