6OOZ

Asymmetric hTNF-alpha

Summary for 6OOZ

• Entry DOI: 10.2210/pdb6ooz/pdb
• Descriptor: Tumor necrosis factor, CHLORIDE ION, (S)-{1-[(2,5-dimethylphenyl)methyl]-1H-benzimidazol-2-yl}(pyridin-4-yl)methanol, ... (4 entities in total)
• Functional Keywords: tumour necrosis factor alpha, tnf, asymmetric, protein-protein interaction inhibitor, rheumatoid arthritis, cytokine
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 3
• Total formula weight: 52490.85

Authors

Arakaki, T.L.,Edwards, T.E.,Fox III, D.,Lecomte, F.,Ceska, T. (deposition date: 2019-04-23, release date: 2019-12-25, Last modification date: 2024-10-30)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.8 Å)