9DJW

X-ray crystal structure of TNFa-VNAR D1 complex

Summary for 9DJW

• Entry DOI: 10.2210/pdb9djw/pdb
• Descriptor: Antigen receptor, Tumor necrosis factor, GLYCEROL, ... (6 entities in total)
• Functional Keywords: toxin, dna binding, deaminase
• Biological source: Squalus acanthias (spiny dogfish); More
• Total number of polymer chains: 60
• Total formula weight: 942443.72

Authors

Ubah, O.C.,Shi, K.,Aihara, H.,Barelle, C.J.,LeBeau, A.M. (deposition date: 2024-09-06, release date: 2025-09-10, Last modification date: 2026-03-25)

Primary citation

Ubah, O.C.,Lake, E.W.,Ott, K.L.,Priyanka, S.,Celeda, S.,West, J.L.,Gunaratne, G.S.,Shi, K.,Moeller, N.H.,Porter, A.J.,Aihara, H.,Kosoff, D.,LeBeau, A.M.,Barelle, C.J.
The structural basis for the selective antagonism of soluble TNF-alpha by shark variable new antigen receptors.
Nat Commun, 17:256-256, 2025

PubMed 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 VNARs do not induce reverse signalling in contrast to currently available therapies. Our findings suggest that neutralization through a unique mechanism may lead to anti-TNF-α agents with an improved safety profile that will benefit high-risk patients.

PubMed: 41318641
DOI: 10.1038/s41467-025-66967-3

Experimental method

X-RAY DIFFRACTION (3.43 Å)