7KP7

asymmetric mTNF-alpha hTNFR1 complex

7KP7 の概要

• エントリーDOI: 10.2210/pdb7kp7/pdb
• 分子名称: Tumor necrosis factor, Tumor necrosis factor receptor superfamily member 1A, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: tumour necrosis factor alpha, tnf, receptor, tnfr1, asymmetric, protein-protein inhibitor, cytokine
• 由来する生物種: Mus musculus (Mouse); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 101811.19

構造登録者

Arakaki, T.L.,Fox III, D.,Edwards, T.E.,Foley, A.,Ceska, T. (登録日: 2020-11-10, 公開日: 2021-01-13, 最終更新日: 2024-10-16)

主引用文献

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

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: 33495441
DOI: 10.1038/s41467-020-20828-3

実験手法

X-RAY DIFFRACTION (2.65 Å)