Targeting the inter-monomeric space of TNFR1 pre-ligand dimers: A novel binding pocket for allosteric modulators.

ABSTRACT: Tumor necrosis factor (TNF) receptor 1 (TNFR1) plays a central role in signal transduction mediating inflammation and cell death associated with autoimmune and neurodegenerative disorders. Inhibition of TNFR1 signaling is a highly sought-after strategy to target these diseases. TNFR1 forms pre-ligand dimers held together by the pre-ligand assembly domain (PLAD), which is essential for receptor signaling. TNFR1 dimers form the crucial points of interaction for the entire receptor signaling complex by connecting TNF ligand bound trimeric receptors. While previous studies have shown the feasibility of disrupting TNFR1 dimeric interactions through competitive mechanism that targets the PLAD, our recent studies have demonstrated that small molecules could also bind PLAD to modulate TNFR1 signal

SUBMITTER: Lo CH 

PROVIDER: S-EPMC11999085 | biostudies-literature | 2025

REPOSITORIES: biostudies-literature