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

Author

Listed:
  • David McMillan

    (UCB Pharma)

  • Carlos Martinez-Fleites

    (UCB Pharma
    GlaxoSmithKline)

  • 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)

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.

Suggested Citation

  • David McMillan & Carlos Martinez-Fleites & John Porter & David Fox & Rachel Davis & Prashant Mori & Tom Ceska & Bruce Carrington & Alastair Lawson & Tim Bourne & James O’Connell, 2021. "Structural insights into the disruption of TNF-TNFR1 signalling by small molecules stabilising a distorted TNF," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20828-3
    DOI: 10.1038/s41467-020-20828-3
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