Anthrax infection is associated with severe illness and high mortality. Protective antigen (PA) is the central component of the anthrax toxin, which is one of two major virulence factors of Bacillus anthracis, the causative agent of anthrax disease. Upon endocytosis, PA opens a pore in the membranes of endosomes, through which the cytotoxic enzymes of the toxin are extruded. The PA pore is formed by a cooperative conformational change in which the membrane-penetrating loops of PA associate, forming a hydrophobic rim that pierces the membrane. Due to its crucial role in anthrax progression, PA is an important target for monoclonal antibody-based therapy. cAb29 is a highly effective neutralizing antibody against PA. Here, the cryo-EM structure of PA in complex with the Fab portion of cAb29 was determined. It was found that cAb29 neutralizes the toxin by clamping the membrane-penetrating loop of PA to the static surface-exposed loop of the D3 domain of the same subunit, thereby preventing pore formation. These results provide the structural basis for the antibody-based neutralization of PA and bring into focus the membrane-penetrating loop of PA as a target for the development of better anti-anthrax vaccines.

中文翻译：

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通过抗体介导的穿膜环吻合来中和炭疽毒素

炭疽感染与严重疾病和高死亡率有关。保护性抗原（PA）是炭疽毒素的核心成分，是炭疽杆菌的两大毒力因子之一，炭疽病的病原体。内吞作用后，PA 在内体膜上打开一个孔，毒素的细胞毒性酶通过该孔排出。PA 孔由协同构象变化形成，其中 PA 的膜穿透环结合，形成刺穿膜的疏水边缘。由于其在炭疽进展中的关键作用，PA 是基于单克隆抗体的治疗的重要目标。cAb29 是一种针对 PA 的高效中和抗体。在这里，确定了与 cAb29 的 Fab 部分复合的 PA 的低温-EM 结构。发现cAb29通过将PA的膜穿透环夹在同一亚基的D3结构域的静态表面暴露环上来中和毒素，从而防止孔形成。