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Autoinhibitory structure of preligand association state implicates a new strategy to attain effective DR5 receptor activation

Cell Res. 2023-01; 
Gang Du, Linlin Zhao, Yumei Zheng, Anissa Belfetmi, Tiantian Cai, Boying Xu, Karen Heyninck, Kim Van Den Heede, Marie-Ange Buyse, Pietro Fontana, Michael Bowman, Lih-Ling Lin, Hao Wu, James Jeiwen Chou
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Plasmid DNA Preparation … the Flag sequence (DYKDDDDK), human DR5 (isoform 1) residues 1–245 (ECD and TMD), and the N- or C-terminal Venus fragment was cloned into the pcDNA 3.1 vector (GenScript). … Get A Quote

摘要

Members of the tumor necrosis factor receptor superfamily (TNFRSF) are important therapeutic targets that can be activated to induce death of cancer cells or stimulate proliferation of immune cells. Although it has long been implicated that these receptors assemble preligand associated states that are required for dominant interference in human disease, such states have so far eluded structural characterization. Here, we find that the ectodomain of death receptor 5 (DR5-ECD), a representative member of TNFRSF, can specifically self-associate when anchored to lipid bilayer, and we report this self-association structure determined by nuclear magnetic resonance (NMR). Unexpectedly, two non-overlapping interaction ... More

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