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

McMillan, David; Martinez-Fleites, Carlos; Porter, John; Fox, David; Davis, Rachel; Mori, Prashant; Ceska, Tom; Carrington, Bruce; Lawson, Alastair; Bourne, Tim; O’Connell, James

doi:10.1038/s41467-020-20828-3

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

Journal Article · Mon Jan 25 00:00:00 UTC 2021 · Nature Communications

DOI: https://doi.org/10.1038/s41467-020-20828-3 · OSTI ID:1767203

^[1]; Martinez-Fleites, Carlos ^[2];

^[1];

^[3]; Davis, Rachel ^[1]; Mori, Prashant ^[1]; Ceska, Tom ^[1]; Carrington, Bruce ^[1]; Lawson, Alastair ^[1]; Bourne, Tim ^[1];

^[1]

UCB Pharma, Slough (United Kingdom)
UCB Pharma, Slough (United Kingdom); GlaxoSmithKline, Stevenage (United Kingdom)
UCB Pharma, Bainbridge Island, WA (United States)

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS); UCB Pharma, Slough (United Kingdom)

Sponsoring Organization:: USDOE

OSTI ID:: 1767203

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 12; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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