Structural insights into the disruption of TNF-TNFR1 signalling by small molecules stabilising a distorted TNF

David McMillan (), Carlos Martinez-Fleites, John Porter, David Fox, Rachel Davis, Prashant Mori, Tom Ceska, Bruce Carrington, Alastair Lawson, Tim Bourne and James O’Connell
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David McMillan: UCB Pharma
Carlos Martinez-Fleites: UCB Pharma
John Porter: UCB Pharma
David Fox: UCB Pharma
Rachel Davis: UCB Pharma
Prashant Mori: UCB Pharma
Tom Ceska: UCB Pharma
Bruce Carrington: UCB Pharma
Alastair Lawson: UCB Pharma
Tim Bourne: UCB Pharma
James O’Connell: UCB Pharma

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20828-3

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DOI: 10.1038/s41467-020-20828-3

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