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5bvp

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Revision as of 07:44, 11 March 2020

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

Structural highlights

5bvp is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
NonStd Res:
Gene:	IL1B, IL1F2 (HUMAN)
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.^[1]

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^[2]

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

References

↑ Van Damme J, De Ley M, Opdenakker G, Billiau A, De Somer P, Van Beeumen J. Homogeneous interferon-inducing 22K factor is related to endogenous pyrogen and interleukin-1. Nature. 1985 Mar 21-27;314(6008):266-8. PMID:3920526
↑ Rondeau JM, Ramage P, Zurini M, Gram H. The molecular mode of action and species specificity of canakinumab, a human monoclonal antibody neutralizing IL-1beta. MAbs. 2015 Aug 18:0. PMID:26284424 doi:http://dx.doi.org/10.1080/19420862.2015.1081323

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5bvp"

@@ Line 1: / Line 1: @@
 ==The molecular mode of action and species specificity of canakinumab, a human monoclonal antibody neutralizing IL-1beta==
-<StructureSection load='5bvp' size='340' side='right' caption='[[5bvp]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
+<StructureSection load='5bvp' size='340' side='right'caption='[[5bvp]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5bvp]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5BVP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5BVP FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5bvp]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5BVP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5BVP FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr>
 <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PCA:PYROGLUTAMIC+ACID'>PCA</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5bvp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5bvp OCA], [http://pdbe.org/5bvp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5bvp RCSB], [http://www.ebi.ac.uk/pdbsum/5bvp PDBsum]</span></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">IL1B, IL1F2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5bvp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5bvp OCA], [http://pdbe.org/5bvp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5bvp RCSB], [http://www.ebi.ac.uk/pdbsum/5bvp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5bvp ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 18: / Line 20: @@
 </div>
 <div class="pdbe-citations 5bvp" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Interleukin 3D structures|Interleukin 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Rondeau, J M]]
 [[Category: Beta trefoil]]

5bvp

From Proteopedia

Revision as of 07:44, 11 March 2020

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

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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