An ancillary carbohydrate recognition domain on ricin toxin's B subunit is the target of receptor-blocking, neutralizing monoclonal antibodies
Authorea (Authorea)(2023)
摘要
Monoclonal antibodies, JB4 and SylH3, neutralize ricin toxin (RT) by inhibiting the galactose-specific lectin activity of the toxin’s B subunit (RTB), which is required for cell attachment and entry. It is not immediately apparent how the antibodies accomplish this feat, considering that RTB consists of two globular domains (D1, D2) each divided into three homologous sub-domains (a, b, g) with the two functional galactosyl-specific carbohydrate recognition domains (CRDs) situated on opposite poles (sub-domains 1a and 2g). Here we report the X-ray crystal structures of JB4 and SylH3 Fab fragments bound to RTB in the context of RT. The structures revealed that neither Fab obstructed or induced detectable conformational alterations in subdomains 1a or 2g. Rather, JB4 and SylH3 Fabs recognize nearly identical epitopes within an ancillary carbohydrate recognition pocket located in subdomain 1β. Despite limited amino acid sequence similarity between SylH3 and JB4 Fabs, each paratope inserts a Phe side chain from heavy (H) chain complementarity determining region (CDR3) into the 1β CRD pocket, resulting in local aromatic stacking interactions that potentially mimic a ligand interaction. Reconciling the fact that stoichiometric amounts of SylH3 and JB4 are sufficient to disarm RTB’s lectin activity without evidence of allostery, we propose that subdomain 1β functions as a “coreceptor” required to stabilize glycan interactions principally mediated by subdomains 1a and 2g. Further investigation into subdomain 1β will yield fundamental insights into the large family of R-type lectins and open novel avenues for countermeasures aimed at preventing toxin uptake into vulnerable tissues and cells.
更多查看译文
关键词
ancillary carbohydrate recognition domain,antibodies,toxin,receptor-blocking
AI 理解论文
溯源树
样例
![](https://originalfileserver.aminer.cn/sys/aminer/pubs/mrt_preview.jpeg)
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要