4gaf | pdb_00004gaf

Crystal structure of EBI-005, a chimera of human IL-1beta and IL-1Ra, bound to human Interleukin-1 receptor type 1

spinqualitylabelsall models 4gaf, resolution 2.15Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4gaf is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: NA, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function IL1B_HUMAN Produced by activated macrophages, IL-1 stimulates thymocyte proliferation by inducing IL-2 release, B-cell maturation and proliferation, and fibroblast growth factor activity. IL-1 proteins are involved in the inflammatory response, being identified as endogenous pyrogens, and are reported to stimulate the release of prostaglandin and collagenase from synovial cells. Publication Abstract from PubMed IL-1 is a key inflammatory and immune mediator in many diseases, including dry-eye disease, and its inhibition is clinically efficacious in rheumatoid arthritis and cryopyrin-associated periodic syndromes. To treat ocular surface disease with a topical biotherapeutic, the uniqueness of the site necessitates consideration of the agent's size, target location, binding kinetics, and thermal stability. Here we chimerized two IL-1 receptor ligands, IL-1beta and IL-1Ra, to create an optimized receptor antagonist, EBI-005, for topical ocular administration. EBI-005 binds its target, IL-1R1, 85-fold more tightly than IL-1Ra, and this increase translates to an approximately 100-fold increase in potency in vivo. EBI-005 preserves the affinity bias of IL-1Ra for IL-1R1 over the decoy receptor (IL-1R2), and, surprisingly, is also more thermally stable than either parental molecule. This rationally designed antagonist represents a unique approach to therapeutic design that can potentially be exploited for other beta-trefoil family proteins in the IL-1 and FGF families. Design of a superior cytokine antagonist for topical ophthalmic use.,Hou J, Townson SA, Kovalchin JT, Masci A, Kiner O, Shu Y, King BM, Schirmer E, Golden K, Thomas C, Garcia KC, Zarbis-Papastoitsis G, Furfine ES, Barnes TM Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):3913-8. doi:, 10.1073/pnas.1217996110. Epub 2013 Feb 19. PMID:23431173 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Interleukin receptor 3D structures

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