6WJ5

Structure of human TRPA1 in complex with inhibitor GDC-0334

6WJ5 の概要

• エントリーDOI: 10.2210/pdb6wj5/pdb
• EMDBエントリー: 21688
• 分子名称: Transient receptor potential cation channel subfamily A member 1, (4R,5S)-4-fluoro-1-[(4-fluorophenyl)sulfonyl]-5-methyl-N-({5-(trifluoromethyl)-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl}methyl)-L-prolinamide (2 entities in total)
• 機能のキーワード: trpa1, channel, inhibitor, antagonist, membrane protein, membrane protein-inhibitor complex, membrane protein/inhibitor
• 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: 292926.47

構造登録者

Rohou, A.,Rouge, L.,Arthur, C.P.,Volgraf, M.,Chen, H. (登録日: 2020-04-11, 公開日: 2021-02-17, 最終更新日: 2024-05-29)

主引用文献

Balestrini, A.,Joseph, V.,Dourado, M.,Reese, R.M.,Shields, S.D.,Rouge, L.,Bravo, D.D.,Chernov-Rogan, T.,Austin, C.D.,Chen, H.,Wang, L.,Villemure, E.,Shore, D.G.M.,Verma, V.A.,Hu, B.,Chen, Y.,Leong, L.,Bjornson, C.,Hotzel, K.,Gogineni, A.,Lee, W.P.,Suto, E.,Wu, X.,Liu, J.,Zhang, J.,Gandham, V.,Wang, J.,Payandeh, J.,Ciferri, C.,Estevez, A.,Arthur, C.P.,Kortmann, J.,Wong, R.L.,Heredia, J.E.,Doerr, J.,Jung, M.,Vander Heiden, J.A.,Roose-Girma, M.,Tam, L.,Barck, K.H.,Carano, R.A.D.,Ding, H.T.,Brillantes, B.,Tam, C.,Yang, X.,Gao, S.S.,Ly, J.Q.,Liu, L.,Chen, L.,Liederer, B.M.,Lin, J.H.,Magnuson, S.,Chen, J.,Hackos, D.H.,Elstrott, J.,Rohou, A.,Safina, B.S.,Volgraf, M.,Bauer, R.N.,Riol-Blanco, L.
A TRPA1 inhibitor suppresses neurogenic inflammation and airway contraction for asthma treatment.
J.Exp.Med., 218:-, 2021

PubMed Abstract: Despite the development of effective therapies, a substantial proportion of asthmatics continue to have uncontrolled symptoms, airflow limitation, and exacerbations. Transient receptor potential cation channel member A1 (TRPA1) agonists are elevated in human asthmatic airways, and in rodents, TRPA1 is involved in the induction of airway inflammation and hyperreactivity. Here, the discovery and early clinical development of GDC-0334, a highly potent, selective, and orally bioavailable TRPA1 antagonist, is described. GDC-0334 inhibited TRPA1 function on airway smooth muscle and sensory neurons, decreasing edema, dermal blood flow (DBF), cough, and allergic airway inflammation in several preclinical species. In a healthy volunteer Phase 1 study, treatment with GDC-0334 reduced TRPA1 agonist-induced DBF, pain, and itch, demonstrating GDC-0334 target engagement in humans. These data provide therapeutic rationale for evaluating TRPA1 inhibition as a clinical therapy for asthma.

PubMed: 33620419
DOI: 10.1084/jem.20201637

実験手法

ELECTRON MICROSCOPY (3.6 Å)