5bvj

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

spinqualitylabelsall models 5bvj, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5bvj is a 8 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: PCA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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.

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