6OOZ

Asymmetric hTNF-alpha

6OOZ の概要

• エントリーDOI: 10.2210/pdb6ooz/pdb
• 分子名称: Tumor necrosis factor, CHLORIDE ION, (S)-{1-[(2,5-dimethylphenyl)methyl]-1H-benzimidazol-2-yl}(pyridin-4-yl)methanol, ... (4 entities in total)
• 機能のキーワード: tumour necrosis factor alpha, tnf, asymmetric, protein-protein interaction inhibitor, rheumatoid arthritis, cytokine
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 52490.85

構造登録者

Arakaki, T.L.,Edwards, T.E.,Fox III, D.,Lecomte, F.,Ceska, T. (登録日: 2019-04-23, 公開日: 2019-12-25, 最終更新日: 2024-10-30)

主引用文献

O'Connell, J.,Porter, J.,Kroeplien, B.,Norman, T.,Rapecki, S.,Davis, R.,McMillan, D.,Arakaki, T.,Burgin, A.,Fox Iii, D.,Ceska, T.,Lecomte, F.,Maloney, A.,Vugler, A.,Carrington, B.,Cossins, B.P.,Bourne, T.,Lawson, A.
Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer.
Nat Commun, 10:5795-5795, 2019

PubMed Abstract: Tumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn's disease. While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for a class of small molecule drugs capable of modulating TNF function by stabilising a naturally sampled, receptor-incompetent conformation of TNF. Furthermore, this approach may prove to be a more general mechanism for inhibiting protein-protein interactions.

PubMed: 31857588
DOI: 10.1038/s41467-019-13616-1

実験手法

X-RAY DIFFRACTION (2.8 Å)