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8iow

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

Structural highlights

8iow is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.2Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

IL6RA_HUMAN Part of the receptor for interleukin 6. Binds to IL6 with low affinity, but does not transduce a signal. Signal activation necessitate an association with IL6ST. Activation may lead to the regulation of the immune response, acute-phase reactions and hematopoiesis.^[1] ^[2] Low concentration of a soluble form of IL6 receptor acts as an agonist of IL6 activity.^[3] ^[4]

Publication Abstract from PubMed

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 A, 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.

Structural insights into IL-6 signaling inhibition by therapeutic antibodies.,Wang M, Chen L, He J, Xia W, Ye Z, She J Cell Rep. 2024 Mar 26;43(3):113819. doi: 10.1016/j.celrep.2024.113819. Epub 2024 , Feb 22. PMID:38393945^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Martens AS, Bode JG, Heinrich PC, Graeve L. The cytoplasmic domain of the interleukin-6 receptor gp80 mediates its basolateral sorting in polarized madin-darby canine kidney cells. J Cell Sci. 2000 Oct;113 ( Pt 20):3593-602. PMID:11017875
↑ Buk DM, Renner O, Graeve L. Increased association with detergent-resistant membranes/lipid rafts of apically targeted mutants of the interleukin-6 receptor gp80. Eur J Cell Biol. 2005 Oct;84(10):819-31. PMID:16270750
↑ Martens AS, Bode JG, Heinrich PC, Graeve L. The cytoplasmic domain of the interleukin-6 receptor gp80 mediates its basolateral sorting in polarized madin-darby canine kidney cells. J Cell Sci. 2000 Oct;113 ( Pt 20):3593-602. PMID:11017875
↑ Buk DM, Renner O, Graeve L. Increased association with detergent-resistant membranes/lipid rafts of apically targeted mutants of the interleukin-6 receptor gp80. Eur J Cell Biol. 2005 Oct;84(10):819-31. PMID:16270750
↑ Wang M, Chen L, He J, Xia W, Ye Z, She J. Structural insights into IL-6 signaling inhibition by therapeutic antibodies. Cell Rep. 2024 Mar 26;43(3):113819. PMID:38393945 doi:10.1016/j.celrep.2024.113819