Structural basis for CSPG4 as a receptor for TcdB and a therapeutic target in Clostridioides difficile infection.
Structural basis for CSPG4 as a receptor for TcdB and a therapeutic target in Clostridioides difficile infection.
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DOI：
10.1038/s41467-021-23878-3
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发表时间：
2021-06-18
影响因子：
16.6
通讯作者：
Jin R
中科院分区：
文献类型：
--
作者：
Chen P;Zeng J;Liu Z;Thaker H;Wang S;Tian S;Zhang J;Tao L;Gutierrez CB;Xing L;Gerhard R;Huang L;Dong M;Jin R
C.艰难梭菌（difficile）是与消化道相关的胃肠道感染的主要原因。两个C。艰难梭菌外毒素（TcdA和TcdB）是与这些感染相关的主要毒力因子，硫酸软骨素蛋白聚糖4（CSPG 4）是TcdB的潜在受体，但其病理生理学相关性和控制识别的分子细节仍然未知。在这里，我们确定的冷冻EM结构的TcdB-CSPG 4复合物，揭示了一个独特的结合位点空间上组成的多个不连续的区域跨越TcdB。选择性破坏CSPG 4结合的突变降低了小鼠中的TcdB毒性，而CSPG 4敲除小鼠在C.艰难感染。我们进一步表明，bezlotoxumab，唯一FDA批准的抗TcdB抗体，通过变构机制阻断CSPG 4结合，但由于其表位的序列变异，它对来自流行性高毒力菌株的许多TcdB变体显示出低中和效力。相比之下，CSPG 4模拟诱饵中和主要的TcdB变体，这表明了开发针对TcdB的广谱治疗剂的策略。硫酸软骨素蛋白聚糖4（CSPG 4）是C.艰难梭菌毒素B（TcdB）。艰难梭菌感染（CDIs）。在这里，TcdB-CSPG 4复合物和CDI小鼠模型的冷冻-EM结构提供了对CSPG 4在CDI中的作用的见解，并提出了靶向TcdB的治疗策略。
C. difficile is a major cause of antibiotic-associated gastrointestinal infections. Two C. difficile exotoxins (TcdA and TcdB) are major virulence factors associated with these infections, and chondroitin sulfate proteoglycan 4 (CSPG4) is a potential receptor for TcdB, but its pathophysiological relevance and the molecular details that govern recognition remain unknown. Here, we determine the cryo-EM structure of a TcdB–CSPG4 complex, revealing a unique binding site spatially composed of multiple discontinuous regions across TcdB. Mutations that selectively disrupt CSPG4 binding reduce TcdB toxicity in mice, while CSPG4-knockout mice show reduced damage to colonic tissues during C. difficile infections. We further show that bezlotoxumab, the only FDA approved anti-TcdB antibody, blocks CSPG4 binding via an allosteric mechanism, but it displays low neutralizing potency on many TcdB variants from epidemic hypervirulent strains due to sequence variations in its epitopes. In contrast, a CSPG4-mimicking decoy neutralizes major TcdB variants, suggesting a strategy to develop broad-spectrum therapeutics against TcdB. Chondroitin sulfate proteoglycan 4 (CSPG4) is a potential receptor for C. difficile toxin B (TcdB) during C. difficile infections (CDIs). Here, the cryo-EM structure of a TcdB–CSPG4 complex and CDI mouse models offer insights into CSPG4 role in CDIs and suggest a therapeutic strategy targeting TcdB.
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DOI：
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发表时间：
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