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TitleStructural insights into IL-6 signaling inhibition by therapeutic antibodies.
Journal, issue, pagesCell Rep, Vol. 43, Issue 3, Page 113819, Year 2024
Publish dateMar 26, 2024
AuthorsMingxing Wang / Long Chen / Jin He / Wenqiang Xia / Zihong Ye / Ji She /
PubMed AbstractAntibody 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 ...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.
External linksCell Rep / PubMed:38393945
MethodsEM (single particle)
Resolution3.2 Å
Structure data

35627

8iow

EMDB-35627, PDB-8iow:
Cryo-EM structure of the sarilumab Fab/IL-6R complex
Method: EM (single particle) / Resolution: 3.2 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • homo sapiens (human)
KeywordsIMMUNE SYSTEM / antibody / IL-6R / structural protein

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