Natural triterpenoid-aided identification of the druggable interface of HMGB1 occupied by TLR4†

IF 4.2 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Pingping Shen, Xuewa Jiang, Yi Kuang, Weiwei Wang, Richa Raj, Wei Wang, Yuyuan Zhu, Xiaochun Zhang, Boyang Yu and Jian Zhang
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Abstract

HMGB1 interacts with TLR4 to activate the inflammatory cascade response, contributing to the pathogenesis of endogenous tissue damage and infection. The immense importance of HMGB1–TLR4 interaction in the immune system has made its binding interface an area of significant interest. To map the binding interface of HMGB1 occupied by TLR4, triterpenoids that disrupt the HMGB1–TLR4 interaction and interfere with HMGB1-induced inflammation were developed. Using the unique triterpenoid PT-22 as a probe along with photoaffinity labeling and site-directed mutagenesis, we found that the binding interface of HMGB1 was responsible for the recognition of TLR4 located on the “L” shaped B-box with K114 as a crucial hot-spot residue. Amazingly, this highly conserved interaction surface overlapped with the antigen-recognition epitope of an anti-HMGB1 antibody. Our findings propose a novel strategy for better understanding the druggable interface of HMGB1 that interacts with TLR4 and provide insights for the rational design of HMGB1–TLR4 PPI inhibitors to fine tune immune responses.

Abstract Image

Abstract Image

天然三萜类化合物辅助鉴定 TLR4 占用的 HMGB1 药物界面
HMGB1 与 TLR4 相互作用,激活炎症级联反应,导致内源性组织损伤和感染的发病机制。HMGB1-TLR4 相互作用在免疫系统中的巨大重要性使其结合界面成为一个备受关注的领域。为了绘制 TLR4 占用的 HMGB1 结合界面,研究人员开发了能破坏 HMGB1-TLR4 相互作用并干扰 HMGB1 诱导的炎症的三萜类化合物。利用独特的三萜类化合物 PT-22 作为探针,配合光亲和标记和定点突变,我们发现 HMGB1 的结合界面负责识别位于 "L "形 B-box 上的 TLR4,其中 K114 是关键的热点残基。令人惊讶的是,这个高度保守的相互作用表面与抗 HMGB1 抗体的抗原识别表位重叠。我们的研究结果提出了一种新的策略,可以更好地了解与 TLR4 相互作用的 HMGB1 的可药用界面,并为合理设计 HMGB1-TLR4 PPI 抑制剂以微调免疫反应提供了启示。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
6.10
自引率
0.00%
发文量
128
审稿时长
10 weeks
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