7JUP

Structure of human TRPA1 in complex with antagonist compound 21

7JUP の概要

• エントリーDOI: 10.2210/pdb7jup/pdb
• EMDBエントリー: 22490
• 分子名称: Transient receptor potential cation channel subfamily A member 1, 1-({3-[(3R,5R)-5-(4-fluorophenyl)oxolan-3-yl]-1,2,4-oxadiazol-5-yl}methyl)-7-methyl-1,7-dihydro-6H-purin-6-one (2 entities in total)
• 機能のキーワード: trpa1, channel, agonist, membrane protein, membrane protein-antagonist complex, membrane protein/antagonist
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 292074.00

構造登録者

Rohou, A.,Rouge, L. (登録日: 2020-08-20, 公開日: 2021-03-31, 最終更新日: 2024-03-06)

主引用文献

Terrett, J.A.,Chen, H.,Shore, D.G.,Villemure, E.,Larouche-Gauthier, R.,Dery, M.,Beaumier, F.,Constantineau-Forget, L.,Grand-Maitre, C.,Lepissier, L.,Ciblat, S.,Sturino, C.,Chen, Y.,Hu, B.,Lu, A.,Wang, Y.,Cridland, A.P.,Ward, S.I.,Hackos, D.H.,Reese, R.M.,Shields, S.D.,Chen, J.,Balestrini, A.,Riol-Blanco, L.,Lee, W.P.,Liu, J.,Suto, E.,Wu, X.,Zhang, J.,Ly, J.Q.,La, H.,Johnson, K.,Baumgardner, M.,Chou, K.J.,Rohou, A.,Rouge, L.,Safina, B.S.,Magnuson, S.,Volgraf, M.
Tetrahydrofuran-Based Transient Receptor Potential Ankyrin 1 (TRPA1) Antagonists: Ligand-Based Discovery, Activity in a Rodent Asthma Model, and Mechanism-of-Action via Cryogenic Electron Microscopy.
J.Med.Chem., 64:3843-3869, 2021

PubMed Abstract: Transient receptor potential ankyrin 1 (TRPA1) is a nonselective calcium-permeable ion channel highly expressed in the primary sensory neurons functioning as a polymodal sensor for exogenous and endogenous stimuli and has generated widespread interest as a target for inhibition due to its implication in neuropathic pain and respiratory disease. Herein, we describe the optimization of a series of potent, selective, and orally bioavailable TRPA1 small molecule antagonists, leading to the discovery of a novel tetrahydrofuran-based linker. Given the balance of physicochemical properties and strong target engagement in a rat AITC-induced pain assay, compound was progressed into a guinea pig ovalbumin asthma model where it exhibited significant dose-dependent reduction of inflammatory response. Furthermore, the structure of the TRPA1 channel bound to compound was determined via cryogenic electron microscopy to a resolution of 3 Å, revealing the binding site and mechanism of action for this class of antagonists.

PubMed: 33749283
DOI: 10.1021/acs.jmedchem.0c02023

実験手法

ELECTRON MICROSCOPY (3.05 Å)