The structural basis for the selective antagonism of soluble TNF-alpha by shark variable new antigen receptors.

ABSTRACT: The pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) is synthesized as transmembrane TNF-α (tmTNF-α) where proteolytic processing releases soluble TNF-α (sTNF-α). tmTNF-α can act as either a ligand by activating TNF receptors, or a receptor that transmits reverse (outside-to-inside) signalling after binding to native receptors. All TNF-α therapies bind tmTNF-α and induce reverse signalling which can result in immunosuppression leading to infection. We present crystal structures of two anti-TNF-α Variable New Antigen Receptors (VNARs) in complex with sTNF-α via two distinct epitopes. The VNAR-D1 recognizes an epitope that selectively engages sTNF-α while VNAR-C4 binds an epitope that partially overlaps with other biologic therapies. In activated CD4⁺ T cells, our VNA

SUBMITTER: Ubah OC 

PROVIDER: S-EPMC12783797 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature