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==== | ==Crystal Structure Of Human Il-1beta In Complex With Antibody Binding Fragment Of IgG26== | ||
<StructureSection load='7chy' size='340' side='right'caption='[[7chy]]' scene=''> | <StructureSection load='7chy' size='340' side='right'caption='[[7chy]], [[Resolution|resolution]] 2.65Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br> | <table><tr><td colspan='2'>[[7chy]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7CHY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7CHY FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7chy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7chy OCA], [https://pdbe.org/7chy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7chy RCSB], [https://www.ebi.ac.uk/pdbsum/7chy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7chy ProSAT]</span></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.65Å</td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7chy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7chy OCA], [https://pdbe.org/7chy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7chy RCSB], [https://www.ebi.ac.uk/pdbsum/7chy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7chy ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/IL1B_HUMAN 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.<ref>PMID:3920526</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Interleukin-1beta (IL-1beta) is a potent pleiotropic cytokine playing a central role in protecting cells from microbial pathogen infection or endogenous stress. After it binds to IL-1RI and recruits IL-1 receptor accessory protein (IL-1RAcP), signaling culminates in activation of NF-kappaB. Many pathophysiological diseases have been attributed to the derailment of IL-1beta regulation. Several blocking reagents have been developed based on two mechanisms: blocking the binding of IL-1beta to IL-1RI or inhibiting the recruitment of IL-1RAcP to the IL-1beta initial complex. In order to simultaneously fulfill these two actions, a human anti-IL-1beta neutralizing antibody IgG26 was screened from human genetic phage-display library and furthered structure-optimized to final version, IgG26AW. IgG26AW has a sub-nanomolar binding affinity for human IL-1beta. We validated IgG26AW-neutralizing antibodies specific for IL-1beta in vivo to prevent human IL-1beta-driving IL-6 elevation in C56BL/6 mice. Mice underwent treatments with IgG26AW in A549 and MDA-MB-231 xenograft mouse cancer models have also been observed with tumor shrank and inhibition of tumor metastasis. The region where IgG26 binds to IL-1beta also overlaps with the position where IL-1RI and IL-1RAcP bind, as revealed by the 26-Fab/IL-1beta complex structure. Meanwhile, SPR experiments showed that IL-1beta bound by IgG26AW prevented the further binding of IL-1RI and IL-1RAcP, which confirmed our inference from the result of protein structure. Therefore, the inhibitory mechanism of IgG26AW is to block the assembly of the IL-1beta/IL-1RI/IL-1RAcP ternary complex which further inhibits downstream signaling. Based on its high affinity, high neutralizing potency, and novel binding epitope simultaneously occupying both IL-1RI and IL-1RAcP residues that bind to IL-1beta, IgG26AW may be a new candidate for treatments of inflammation-related diseases or for complementary treatments of cancers in which the role of IL-1beta is critical to pathogenesis. | |||
Structure-based Development of Human Interleukin-1beta-Specific Antibody That Simultaneously Inhibits Binding to Both IL-1RI and IL-1RAcP.,Kuo WC, Lee CC, Chang YW, Pang W, Chen HS, Hou SC, Lo SY, Yang AS, Wang AH J Mol Biol. 2021 Feb 19;433(4):166766. doi: 10.1016/j.jmb.2020.166766. Epub 2020 , Dec 24. PMID:33359099<ref>PMID:33359099</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7chy" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Antibody 3D structures|Antibody 3D structures]] | |||
*[[Interleukin 3D structures|Interleukin 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Kuo WC]] | ||
[[Category: Lee CC]] | |||
[[Category: Wang AHJ]] | |||
Revision as of 19:08, 29 November 2023
Crystal Structure Of Human Il-1beta In Complex With Antibody Binding Fragment Of IgG26Crystal Structure Of Human Il-1beta In Complex With Antibody Binding Fragment Of IgG26
Structural highlights
FunctionIL1B_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 PubMedInterleukin-1beta (IL-1beta) is a potent pleiotropic cytokine playing a central role in protecting cells from microbial pathogen infection or endogenous stress. After it binds to IL-1RI and recruits IL-1 receptor accessory protein (IL-1RAcP), signaling culminates in activation of NF-kappaB. Many pathophysiological diseases have been attributed to the derailment of IL-1beta regulation. Several blocking reagents have been developed based on two mechanisms: blocking the binding of IL-1beta to IL-1RI or inhibiting the recruitment of IL-1RAcP to the IL-1beta initial complex. In order to simultaneously fulfill these two actions, a human anti-IL-1beta neutralizing antibody IgG26 was screened from human genetic phage-display library and furthered structure-optimized to final version, IgG26AW. IgG26AW has a sub-nanomolar binding affinity for human IL-1beta. We validated IgG26AW-neutralizing antibodies specific for IL-1beta in vivo to prevent human IL-1beta-driving IL-6 elevation in C56BL/6 mice. Mice underwent treatments with IgG26AW in A549 and MDA-MB-231 xenograft mouse cancer models have also been observed with tumor shrank and inhibition of tumor metastasis. The region where IgG26 binds to IL-1beta also overlaps with the position where IL-1RI and IL-1RAcP bind, as revealed by the 26-Fab/IL-1beta complex structure. Meanwhile, SPR experiments showed that IL-1beta bound by IgG26AW prevented the further binding of IL-1RI and IL-1RAcP, which confirmed our inference from the result of protein structure. Therefore, the inhibitory mechanism of IgG26AW is to block the assembly of the IL-1beta/IL-1RI/IL-1RAcP ternary complex which further inhibits downstream signaling. Based on its high affinity, high neutralizing potency, and novel binding epitope simultaneously occupying both IL-1RI and IL-1RAcP residues that bind to IL-1beta, IgG26AW may be a new candidate for treatments of inflammation-related diseases or for complementary treatments of cancers in which the role of IL-1beta is critical to pathogenesis. Structure-based Development of Human Interleukin-1beta-Specific Antibody That Simultaneously Inhibits Binding to Both IL-1RI and IL-1RAcP.,Kuo WC, Lee CC, Chang YW, Pang W, Chen HS, Hou SC, Lo SY, Yang AS, Wang AH J Mol Biol. 2021 Feb 19;433(4):166766. doi: 10.1016/j.jmb.2020.166766. Epub 2020 , Dec 24. PMID:33359099[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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