TNF receptors: Structure-function relationships and therapeutic targeting strategies

Tumor necrosis factor receptors (TNFR1 and TNFR2) play key roles in mediating inflammatory response and cell death signaling, which are associated with autoimmune disorders, neurodegenerative diseases, and cancers. The structure-function relationships of TNF receptors and their ligands determine the activation or inhibition of downstream signaling pathways. Available crystal structures have provided critical insights into the therapeutic targeting strategies of TNF receptors and their signaling networks. In this review, we discuss the potential of targeting receptor-ligand and receptor-receptor interactions in a competitive manner as well as perturbing receptor conformational dynamics through an allosteric mechanism to modulate TNF receptor signaling. We propose that conformational states of TNF receptors can act as a molecular switch in determining their functions and are important therapeutic targets. The knowledge of the structure-function relationships of TNF receptors can be applied to translational high-throughput drug screening and design of novel receptor-specific modulators with enhanced pharmacological properties.