7KP9

asymmetric hTNF-alpha

Summary for 7KP9

• Entry DOI: 10.2210/pdb7kp9/pdb
• Descriptor: Tumor necrosis factor, 1-{[2-(difluoromethoxy)phenyl]methyl}-2-methyl-6-[6-(piperazin-1-yl)pyridin-3-yl]-1H-benzimidazole (3 entities in total)
• Functional Keywords: tumour necrosis factor alpha, tnf, asymmetric, protein-protein inhibitor, cytokine
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 3
• Total formula weight: 52822.70

Authors

Arakaki, T.L.,Abendroth, J.,Fairman, J.W.,Foley, A.,Ceska, T. (deposition date: 2020-11-10, release date: 2021-01-13, Last modification date: 2024-10-16)

Primary citation

McMillan, D.,Martinez-Fleites, C.,Porter, J.,Fox 3rd, D.,Davis, R.,Mori, P.,Ceska, T.,Carrington, B.,Lawson, A.,Bourne, T.,O'Connell, J.
Structural insights into the disruption of TNF-TNFR1 signalling by small molecules stabilising a distorted TNF.
Nat Commun, 12:582-582, 2021

PubMed Abstract: Tumour necrosis factor (TNF) is a trimeric protein which signals through two membrane receptors, TNFR1 and TNFR2. Previously, we identified small molecules that inhibit human TNF by stabilising a distorted trimer and reduce the number of receptors bound to TNF from three to two. Here we present a biochemical and structural characterisation of the small molecule-stabilised TNF-TNFR1 complex, providing insights into how a distorted TNF trimer can alter signalling function. We demonstrate that the inhibitors reduce the binding affinity of TNF to the third TNFR1 molecule. In support of this, we show by X-ray crystallography that the inhibitor-bound, distorted, TNF trimer forms a complex with a dimer of TNFR1 molecules. This observation, along with data from a solution-based network assembly assay, leads us to suggest a model for TNF signalling based on TNF-TNFR1 clusters, which are disrupted by small molecule inhibitors.

PubMed: 33495441
DOI: 10.1038/s41467-020-20828-3

Experimental method

X-RAY DIFFRACTION (2.15 Å)