Document Type
Article
Subject Area(s)
Algorithms; Animals; Binding, Competitive (drug effects); Humans; Models, Molecular; Protein Binding (drug effects); Protein Conformation (drug effects); Protein Multimerization (drug effects); Receptors, Tumor Necrosis Factor, Type I (chemistry, metabolism); Signal Transduction (drug effects); Small Molecule Libraries (chemistry, pharmacology); Tumor Necrosis Factor-alpha (chemistry, metabolism)
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.
Digital Object Identifier (DOI)
Publication Info
Published in Nature Communications, Volume 12, Issue 582, 2021, pages 582-.
Rights
© The Author(s) 2021 This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
APA Citation
McMillan, D., Martinez-Fleites, C., Porter, J., Fox, D., Davis, R., Mori, P., Ceska, T., Carrington, B., Lawson, A., Bourne, T., & O’Connell, J. (2021). Structural insights into the disruption of TNF-TNFR1 signalling by small molecules stabilising a distorted TNF. Nature Communications, 12(1). https://doi.org/10.1038/s41467-020-20828-3