Research ArticlePharmacology

Noncompetitive inhibitors of TNFR1 probe conformational activation states

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Science Signaling  30 Jul 2019:
Vol. 12, Issue 592, eaav5637
DOI: 10.1126/scisignal.aav5637

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Building better TNFR1 blockers

The cytokine TNFα mediates inflammation that is critical for fighting infections and tumors, but when present in excessive amounts, it can cause autoimmune diseases. Lo et al. identified several small molecules that inhibited TNFR1, a receptor for TNFα. Unlike other previously characterized TNFR1 blockers, the authors’ most effective candidates not only showed high affinity for TNFR1 but also potently inhibited the activation of NF-κB, a downstream effector of TNFR1. Instead of blocking the binding of TNFα or the dimerization of TNFR1, the authors’ candidate molecules stabilized inactive conformations of the receptor. Further optimization of the lead molecules may generate TNFR1 inhibitors that are cheaper and lack the dangerous side effects of the currently available biologics that target TNFα.

Abstract

Tumor necrosis factor receptor 1 (TNFR1) is a central mediator of the inflammatory pathway and is associated with several autoimmune diseases such as rheumatoid arthritis. A revision to the canonical model of TNFR1 activation suggests that activation involves conformational rearrangements of preassembled receptor dimers. Here, we identified small-molecule allosteric inhibitors of TNFR1 activation and probed receptor dimerization and function. Specifically, we used a fluorescence lifetime–based high-throughput screen and biochemical, biophysical, and cellular assays to identify small molecules that noncompetitively inhibited the receptor without reducing ligand affinity or disrupting receptor dimerization. We also found that residues in the ligand-binding loop that are critical to the dynamic coupling between the extracellular and the transmembrane domains played a key gatekeeper role in the conformational dynamics associated with signal propagation. Last, using a simple structure-activity relationship analysis, we demonstrated that these newly found molecules could be further optimized for improved potency and specificity. Together, these data solidify and deepen the new model for TNFR1 activation.

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