8upa

Structure of gp130 in complex with a de novo designed IL-6 mimetic

spinqualitylabelsall models 8upa, resolution 3.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8upa is a 4 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.3Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function IL6RB_HUMAN Signal-transducing molecule. The receptor systems for IL6, LIF, OSM, CNTF, IL11, CTF1 and BSF3 can utilize gp130 for initiating signal transmission. Binds to IL6/IL6R (alpha chain) complex, resulting in the formation of high-affinity IL6 binding sites, and transduces the signal. Does not bind IL6. May have a role in embryonic development (By similarity). The type I OSM receptor is capable of transducing OSM-specific signaling events. Publication Abstract from PubMed Cytokine release syndrome (CRS), commonly known as cytokine storm, is an acute systemic inflammatory response that is a significant global health threat. Interleukin-6 (IL-6) and interleukin-1 (IL-1) are key pro-inflammatory cytokines involved in CRS and are hence critical therapeutic targets. Current antagonists, such as tocilizumab and anakinra, target IL-6R/IL-1R but have limitations due to their long half-life and systemic anti-inflammatory effects, making them less suitable for acute or localized treatments. Here we present the de novo design of small protein antagonists that prevent IL-1 and IL-6 from interacting with their receptors to activate signaling. The designed proteins bind to the IL-6R, GP130 (an IL-6 co-receptor), and IL-1R1 receptor subunits with binding affinities in the picomolar to low-nanomolar range. X-ray crystallography studies reveal that the structures of these antagonists closely match their computational design models. In a human cardiac organoid disease model, the IL-1R antagonists demonstrated protective effects against inflammation and cardiac damage induced by IL-1beta. These minibinders show promise for administration via subcutaneous injection or intranasal/inhaled routes to mitigate acute cytokine storm effects. De novo design of miniprotein antagonists of cytokine storm inducers.,Huang B, Coventry B, Borowska MT, Arhontoulis DC, Exposit M, Abedi M, Jude KM, Halabiya SF, Allen A, Cordray C, Goreshnik I, Ahlrichs M, Chan S, Tunggal H, DeWitt M, Hyams N, Carter L, Stewart L, Fuller DH, Mei Y, Garcia KC, Baker D Nat Commun. 2024 Aug 16;15(1):7064. doi: 10.1038/s41467-024-50919-4. PMID:39152100 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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