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Publication Abstract from PubMed

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.

Structural insights into the disruption of TNF-TNFR1 signalling by small molecules stabilising a distorted TNF.,McMillan D, Martinez-Fleites C, Porter J, Fox D 3rd, Davis R, Mori P, Ceska T, Carrington B, Lawson A, Bourne T, O'Connell J Nat Commun. 2021 Jan 25;12(1):582. doi: 10.1038/s41467-020-20828-3. PMID:33495441^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.