7KP8
asymmetric mTNF-alpha hTNFR1 complex
Summary for 7KP8
| Entry DOI | 10.2210/pdb7kp8/pdb |
| Descriptor | Tumor necrosis factor, Tumor necrosis factor receptor superfamily member 1A, 1-{[2-(difluoromethoxy)phenyl]methyl}-2-methyl-6-[6-(piperazin-1-yl)pyridin-3-yl]-1H-benzimidazole, ... (4 entities in total) |
| Functional Keywords | tumour necrosis factor alpha, tnf, receptor, tnfr1, asymmetric, protein-protein inhibitor, cytokine |
| Biological source | Mus musculus (Mouse) More |
| Total number of polymer chains | 5 |
| Total formula weight | 81527.11 |
| Authors | Arakaki, T.L.,Fox III, D.,Edwards, T.E.,Foley, A.,Ceska, T. (deposition date: 2020-11-10, release date: 2021-01-13, Last modification date: 2024-10-16) |
| Primary citation | McMillan, D.,Martinez-Fleites, C.,Porter, J.,Fox 3rd, D.,Davis, R.,Mori, P.,Ceska, T.,Carrington, B.,Lawson, A.,Bourne, T.,O'Connell, J. Structural insights into the disruption of TNF-TNFR1 signalling by small molecules stabilising a distorted TNF. Nat Commun, 12:582-582, 2021 Cited by PubMed 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. PubMed: 33495441DOI: 10.1038/s41467-020-20828-3 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.15 Å) |
Structure validation
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