7chz

From Proteopedia

Crystal Structure Of Human Il-1beta In Complex With Antibody Binding Fragment Of IgG26A

Structural highlights

7chz 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.
Method:	X-ray diffraction, Resolution 2.5Å
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) 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.

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
↑ Kuo WC, Lee CC, Chang YW, Pang W, Chen HS, Hou SC, Lo SY, Yang AS, Wang AH. Structure-based Development of Human Interleukin-1β-Specific Antibody That Simultaneously Inhibits Binding to Both IL-1RI and IL-1RAcP. J Mol Biol. 2021 Feb 19;433(4):166766. PMID:33359099 doi:10.1016/j.jmb.2020.166766