Structural basis of signaling complex inhibition by IL-6 domain-swapped dimers

Structure. 2025. Vol. 33. No. 1. P. 171–180.e5.

Yudenko A., Bukhdruker S., Shishkin P., Rodin S., Burtseva A., Petrov A., Pigareva N., Sokolov A., Zinovev E., Eliseev I., Remeeva A., Marin E., Mishin A., Gordeliy V., Gushchin I., Ischenko A., Borshchevskiy V.

Interleukin-6 (IL-6) is amultifaceted cytokine essential inmany immune systemprocesses andtheir regulation. It also plays a key role in hematopoiesis, and in triggering the acute phase reaction. IL-6 overproduction is critical in chronic inflammation associated with autoimmune diseases like rheumatoid arthritis and contributes to cytokine storms in COVID-19 patients. Over 20 years ago, researchers proposed that IL-6, which is typicallymonomeric, can also formdimers via a domain-swap mechanism, with indirect evidence supporting their existence. The physiological significance of IL-6 dimers was shown in B-cell chronic lymphocytic leukemia. However, no structures have been reported so far. Here, we present the crystal structure of an IL-6 domain-swapped dimer that computational approaches could not predict. The structure explains why the IL-6 dimer is antagonistic to the IL-6 monomer in signaling complex formation and provides insights for IL-6 targeted therapies.

Keywords: Structure, Cytokine, Antibody, Dimerization, AlphaFold, domain-swap, fragment antigen-binding, gp130, IL-6, interleukin 6

Publication based on the results of: Molecular evolution, protein motions and computational molecular modeling (2024)