The structural basis of Salmonella A(2)B(5) toxin neutralization by antibodies targeting the glycan-receptor binding subunits.
The structural basis of Salmonella A(2)B(5) toxin neutralization by antibodies targeting the glycan-receptor binding subunits.
复制标题
DOI：
10.1016/j.celrep.2021.109654
复制
发表时间：
2021-09-07
期刊：
影响因子：
8.8
通讯作者：
Song J
中科院分区：
文献类型：
--
作者：
Nguyen T;Richards AF;Neupane DP;Feathers JR;Yang YA;Sim JH;Byun H;Lee S;Ahn C;Van Slyke G;Fromme JC;Mantis NJ;Song J
许多细菌病原体分泌A(2)B5毒素，包括两个功能不同但互补的“A”和“B”亚基，使病原体在感染期间受益。类似凝集素的五聚体B亚单位识别特定的宿主聚糖，将毒素传递到目标宿主细胞中。在这里，我们提供了中和抗体的分子机制，这些中和抗体有可能结合到所有的聚糖受体结合位点，从而完全抑制毒素与宿主细胞的结合，从而抑制毒素发挥这种作用。基于低温电子显微镜（cro - em）的分析表明，毒素A亚基向毒素B五聚体一侧倾斜的位置抑制了中和抗体与侧位表位的结合，使得一些聚糖受体结合位点仍然可用于毒素结合和内吞噬过程，这与识别远侧位表位的对应抗体明显不同。这些结果突出了毒素-抗体相互作用的其他特征，并为抗毒素策略提供了重要的见解。Nguyen等人发现针对聚糖受体结合B亚基的毒素中和抗体可根据其表位位置分为两类。他们描述了这两类如何表现出显着不同的中和效果，这一特征似乎在a (2)B5毒素中共享，因此他们为抗毒素策略提供了见解。
Many bacterial pathogens secrete A(2)B5 toxins comprising two functionally distinct yet complementary “A” and “B” subunits to benefit the pathogens during infection. The lectin-like pentameric B subunits recognize specific sets of host glycans to deliver the toxin into target host cells. Here, we offer the molecular mechanism by which neutralizing antibodies, which have the potential to bind to all glycan-receptor binding sites and thus completely inhibit toxin binding to host cells, are inhibited from exerting this action. Cryogenic electron microscopy (cryo-EM)-based analyses indicate that the skewed positioning of the toxin A subunit(s) toward one side of the toxin B pentamer inhibited neutralizing antibody binding to the laterally located epitopes, rendering some glycan-receptor binding sites that remained available for the toxin binding and endocytosis process, which is strikingly different from the counterpart antibodies recognizing the far side-located epitopes. These results highlight additional features of the toxin-antibody interactions and offer important insights into anti-toxin strategies. Nguyen et al. find that toxin-neutralizing antibodies targeting glycan-receptor binding B subunits can be split into two classes based on their epitope locations. They describe how these two classes exhibit significantly different neutralizing efficacies, a feature that appears to be shared among A(2)B5 toxins, and thus they provide insights into anti-toxin strategies.
登录
查看更多内容
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
48
作者：
Punjani, Ali;Rubinstein, John L.;Brubaker, Marcus A.
通讯作者：
Brubaker, Marcus A.
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
6.7
作者：
Chang, Shu-Jung;Jin, Sheng Chih;Galan, Jorge E.
通讯作者：
Galan, Jorge E.
影响因子：
30.3
作者：
Lee, Sohyoung;Yang, Yi-An;Song, Jeongmin
通讯作者：
Song, Jeongmin