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对Clostridioides difficile毒素B和FZD相互作用的结构和功能洞察₇

Julia Kinsolving¹, Julien Bous¹, Pawel Kozielewicz¹

¹Karolinska Institutet, Department Physiology & Pharmacology, Sec. Receptor Biology & Signaling, Biomedicum, 17165 Stockholm, Sweden.

|February 3, 2024

概括

克洛斯特里迪奥伊德困难毒素B (TcdB) 通过结构变化与Frizzled受体结合. 贝兹洛托克苏马布通过稳定不活跃的TcdB形式来破坏这种结合,为感染治疗提供了洞察力.

科学领域:

微生物学微生物学
结构生物学结构生物学
药理学药理学是指药理学的学科.

背景情况:

Clostridioides difficile B毒素 (TcdB) 是C. difficile感染中的一个关键的毒性因素.
TcdB利用Frizzled (FZD) 家族的G蛋白结合受体,包括FZD1,FZD2和FZD7,进入细胞.
了解TcdB-FZD相互作用对于开发向疗法至关重要.

研究的目的:

阐明TcdB与Frizzled受体相互作用的结构基础.
研究贝兹洛托马布中和TcdB的机制.
探索TcdB形态动态在受体结合和病变发生中的作用.

主要方法:

活细胞测定测量TcdB-FZD亲和力.
低温电子显微镜 (cryo-EM) 用于单独确定TcdB的结构,并与FZD7.7复合.
对TcdB结构重组和形状动态的分析.

主要成果:

低温EM结构显示,在FZD结合时,TcdB的重复性多域发生了显著的重组.
贝兹洛托克苏马布优先结合阿波-TcdB结构,抑制FZD7相互作用.
TcdB的结构动力学影响其孔形成区域的稳定性.

结论:

TcdB与Frizzled受体的结合是由大型结构重组所启动的.
贝兹洛托克苏马布通过稳定不活跃的TcdB构造而起作用,防止受体参与.
对于TcdB的受体识别和病原性活动来说,TcdB的形态灵活性至关重要.

关键词:

科普:分子生物学分子生物学克洛斯特里迪奥伊德斯困难菌毛的毛的在NanoBRET中使用NanoBRET.这是一种细菌毒素.具有约束力的试验.F类GPCR的GPCR可以使用.结肠结肠结肠结肠是什么意思低温电磁波冷却器 (Cryo-EM) 是一个非常好的方法.我们的肠道是肠道.蛋白质结构蛋白质结构

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