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Structural insights into the disruption of TNF-TNFR1 signalling by small molecules stabilising a distorted TNF
- Source :
- Nature Communications, Vol 12, Iss 1, Pp 1-12 (2021), Nature Communications
- Publication Year :
- 2021
- Publisher :
- Nature Portfolio, 2021.
-
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.<br />Small molecules stabilising a distorted TNF trimer can inhibit TNF signaling, but the underlying mechanism is unclear. Here, the authors characterize the inhibitor-bound TNF-receptor complex structurally and biochemically, showing that the inhibitors alter TNF-receptor binding stoichiometry and cluster formation.
- Subjects :
- 0301 basic medicine
Models, Molecular
Protein Conformation
Dimer
Science
General Physics and Astronomy
Trimer
Binding, Competitive
General Biochemistry, Genetics and Molecular Biology
Article
Small Molecule Libraries
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Cell surface receptor
Molecule
Animals
Humans
Receptor
X-ray crystallography
Multidisciplinary
Mass spectrometry
Chemistry
Tumor Necrosis Factor-alpha
Tumour-necrosis factors
food and beverages
General Chemistry
respiratory system
Small molecule
030104 developmental biology
Receptors, Tumor Necrosis Factor, Type I
Biophysics
Tumor necrosis factor alpha
Extracellular signalling molecules
Protein Multimerization
030217 neurology & neurosurgery
Function (biology)
Algorithms
Protein Binding
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 12
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....82ebdbf59199229fb62a0881c6acd42c