5bvp

The molecular mode of action and species specificity of canakinumab, a human monoclonal antibody neutralizing IL-1beta

spinqualitylabelsall models 5bvp, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5bvp is a 3 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: CL, PCA 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 Interleukin-1beta (IL-1beta) plays a key role in autoinflammatory diseases, such as systemic juvenile idiopathic arthritis (sJIA) or cryopyrin-associated periodic syndrome (CAPS). Canakinumab, a human monoclonal anti-IL-1beta antibody, was recently approved for human use under the brand name Ilaris(R). Canakinumab does not cross-react with IL-1beta from mouse, rat, rabbit, or macaques. The crystal structure of the canakinumab Fab bound to human IL-1beta was determined in an attempt to rationalize the species specificity. The X-ray analysis reveals a complex surface epitope with an intricate network of well-ordered water molecules at the antibody-antigen interface. The canakinumab paratope is largely pre-organized, as demonstrated by the structure determination of the free Fab. Glu 64 of human IL-1beta is a pivotal epitope residue explaining the exquisite species specificity of canakinumab. We identified marmoset as the only non-human primate species that carries Glu 64 in its IL-1beta and demonstrates full cross-reactivity of canakinumab, thereby enabling toxicological studies in this species. As demonstrated by the X-ray structure of the complex with IL-1beta, canakinumab binds IL-1beta on the opposite side with respect to the IL-1RAcP binding site, and in an approximately orthogonal orientation with respect to IL-1RI. However, the antibody and IL-1RI binding sites slightly overlap and the VH region of canakinumab would sterically interfere with the D1 domain of IL-1RI, as shown by a structural overlay with the IL-1beta:IL-1RI complex. Therefore, direct competition with IL-1RI for IL-1beta binding is the molecular mechanism of neutralization by canakinumab, which is also confirmed by competition assays with recombinant IL-1RI and IL-1RII. The molecular mode of action and species specificity of canakinumab, a human monoclonal antibody neutralizing IL-1beta.,Rondeau JM, Ramage P, Zurini M, Gram H MAbs. 2015 Aug 18:0. PMID:26284424 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Interleukin 3D structures

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