Academic Journal
Structural insights into the disruption of TNF-TNFR1 signalling by small molecules stabilising a distorted TNF
| Title: | Structural insights into the disruption of TNF-TNFR1 signalling by small molecules stabilising a distorted TNF |
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| Authors: | David A. Fox, Alastair D. G. Lawson, Rachel Davis, Carlos Martinez-Fleites, Tim Bourne, Tom Ceska, David McMillan, Bruce Carrington, John Robert Porter, O'connell James Philip, Prashant Mori |
| Source: | Nat Commun Nature Communications, Vol 12, Iss 1, Pp 1-12 (2021) |
| Publisher Information: | Springer Science and Business Media LLC, 2021. |
| Publication Year: | 2021 |
| Subject Terms: | Models, Molecular, 0301 basic medicine, tumor, pharmacology), Protein Conformation, Science, TNF-TNFR1, TNF, Binding, Competitive, Article, Small Molecule Libraries, 03 medical and health sciences, Protein Multimerization (drug effects), Models, Receptors, Animals, Humans, molecules, Tumor Necrosis Factor-alpha (chemistry, 0303 health sciences, metabolism), Tumor Necrosis Factor-alpha, Protein Binding (drug effects), Protein Conformation (drug effects), Molecular, Type I (chemistry, Binding, Receptors, Tumor Necrosis Factor, Type I, Signal Transduction (drug effects), Tumour necrosis factor, Protein Multimerization, Competitive (drug effects), Tumor Necrosis Factor, Small Molecule Libraries (chemistry, Public Health Education and Promotion, Algorithms, Protein Binding, Signal Transduction |
| Description: | 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. |
| Document Type: | Article Other literature type |
| File Description: | application/pdf |
| Language: | English |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-020-20828-3 |
| DOI: | 10.1038/s41467-020-20828-3; |
| Access URL: | https://www.nature.com/articles/s41467-020-20828-3.pdf https://pubmed.ncbi.nlm.nih.gov/33495441 https://doaj.org/article/7b680bc50b1f4b8588a84e2e0adb588a https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835368/ https://www.nature.com/articles/s41467-020-20828-3 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835368/ https://europepmc.org/article/PMC/PMC7835368 https://pubmed.ncbi.nlm.nih.gov/33495441/ https://www.nature.com/articles/s41467-020-20828-3.pdf |
| Rights: | CC BY |
| Accession Number: | edsair.doi.dedup.....82ebdbf59199229fb62a0881c6acd42c |
| Database: | OpenAIRE |
| ISSN: | 20411723 |
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| DOI: | 10.1038/s41467-020-20828-3 |