8J6F

Cryo-EM structure of the Tocilizumab Fab/IL-6R complex

Summary for 8J6F

• Entry DOI: 10.2210/pdb8j6f/pdb
• EMDB information: 36003
• Descriptor: Heavy chain of Tocilizumab Fab, Light chain of Tocilizumab Fab, Interleukin-6 receptor subunit alpha, ... (5 entities in total)
• Functional Keywords: antibody, il-6r, structural protein, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 89305.16

Authors

She, J.,Chen, L. (deposition date: 2023-04-25, release date: 2024-03-27, Last modification date: 2025-06-25)

Primary citation

Wang, M.,Chen, L.,He, J.,Xia, W.,Ye, Z.,She, J.
Structural insights into IL-6 signaling inhibition by therapeutic antibodies.
Cell Rep, 43:113819-113819, 2024

PubMed Abstract: Antibody inhibitors of the interleukin-6 (IL-6) signaling pathway, such as tocilizumab and sarilumab, have been used to treat rheumatoid arthritis, chimeric antigen receptor T cell-induced cytokine storm, and severe COVID-19 pneumonia. Here, we solve the cryogenic electron microscopy structures of sarilumab and tocilizumab in complex with IL-6R to resolutions of 3.2 and 3.3 Å, respectively. These structures reveal that both tocilizumab and sarilumab bind to the D3 domain of IL-6R. The binding surfaces of the two antibodies largely overlap, but the detailed interactions are different. Functional studies of various mutants show results consistent with our structural analysis of the antibodies and IL-6R interactions. Structural comparisons with the IL-6/IL-6R/gp130 complex indicate that sarilumab and tocilizumab probably inhibit IL-6/IL-6R signaling by competing for the IL-6 binding site. In summary, this work reveals the antibody-blocking mechanism of the IL-6 signaling pathway and paves the way for future antibody discovery.

PubMed: 38393945
DOI: 10.1016/j.celrep.2024.113819

Experimental method

ELECTRON MICROSCOPY (3.3 Å)