7CHY

Crystal Structure Of Human Il-1beta In Complex With Antibody Binding Fragment Of IgG26

7CHY の概要

• エントリーDOI: 10.2210/pdb7chy/pdb
• 分子名称: light chain of antibody binding fragment of IgG26, heavy chain of antibody binding fragment of IgG26, Interleukin-1 beta, ... (4 entities in total)
• 機能のキーワード: complex, antibody, interleukin-1beta, immunosuppressant
• 由来する生物種: Homo sapiens; 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 66483.53

構造登録者

Lee, C.C.,Wang, A.H.J.,Kuo, W.C. (登録日: 2020-07-06, 公開日: 2021-01-13, 最終更新日: 2024-10-16)

主引用文献

Kuo, W.C.,Lee, C.C.,Chang, Y.W.,Pang, W.,Chen, H.S.,Hou, S.C.,Lo, S.Y.,Yang, A.S.,Wang, A.H.
Structure-based Development of Human Interleukin-1 beta-Specific Antibody That Simultaneously Inhibits Binding to Both IL-1RI and IL-1RAcP.
J.Mol.Biol., 433:166766-166766, 2020

PubMed Abstract: Interleukin-1β (IL-1β) 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-κB. Many pathophysiological diseases have been attributed to the derailment of IL-1β regulation. Several blocking reagents have been developed based on two mechanisms: blocking the binding of IL-1β to IL-1RI or inhibiting the recruitment of IL-1RAcP to the IL-1β initial complex. In order to simultaneously fulfill these two actions, a human anti-IL-1β 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-1β. We validated IgG26AW-neutralizing antibodies specific for IL-1β in vivo to prevent human IL-1β-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-1β also overlaps with the position where IL-1RI and IL-1RAcP bind, as revealed by the 26-Fab/IL-1β complex structure. Meanwhile, SPR experiments showed that IL-1β 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-1β/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-1β, IgG26AW may be a new candidate for treatments of inflammation-related diseases or for complementary treatments of cancers in which the role of IL-1β is critical to pathogenesis.

PubMed: 33359099
DOI: 10.1016/j.jmb.2020.166766

実験手法

X-RAY DIFFRACTION (2.65 Å)