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首页> 外文期刊>Journal of Molecular Biology >Crystal structures of ricin toxin's enzymatic subunit (RTA) in complex with neutralizing and non-neutralizing single-chain antibodies
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Crystal structures of ricin toxin's enzymatic subunit (RTA) in complex with neutralizing and non-neutralizing single-chain antibodies

机译：蓖麻毒素毒素的酶亚基（RTA）的晶体结构与中和非中和单链抗体复合

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摘要

Ricin is a select agent toxin and a member of the RNA N-glycosidase family of medically important plant and bacterial ribosome-inactivating proteins. In this study, we determined X-ray crystal structures of the enzymatic subunit of ricin (RTA) in complex with the antigen binding domains (VHH) of five unique single-chain monoclonal antibodies that differ in their respective toxin-neutralizing activities. None of the VHHs made direct contact with residues involved in RTA's RNA N-glycosidase activity or induced notable allosteric changes in the toxin's subunit. Rather, the five VHHs had overlapping structural epitopes on the surface of the toxin and differed in the degree to which they made contact with prominent structural elements in two folding domains of the RTA. In general, RTA interactions were influenced most by the VHH CDR3 (CDR, complementarity-determining region) elements, with the most potent neutralizing antibody having the shortest and most conformationally constrained CDR3. These structures provide unique insights into the mechanisms underlying toxin neutralization and provide critically important information required for the rational design of ricin toxin subunit vaccines.
机译：蓖麻毒素是一种选择剂毒素，是医学上重要的植物和细菌核糖体失活蛋白的RNA N-糖苷酶家族的成员。在这项研究中，我们确定了蓖麻毒素酶亚基（RTA）的X射线晶体结构与五个独特的单链单克隆抗体的抗原结合域（VHH）的复合物，它们的毒素中和活性不同。没有一个VHH与RTA的RNA N-糖苷酶活性涉及的残基直接接触，或在毒素的亚基中引起明显的变构变化。而是，五个VHH在毒素表面上具有重叠的结构表位，并且它们与RTA的两个折叠域中的突出结构元素接触的程度不同。通常，RTA相互作用受VHH CDR3（CDR，互补决定区）元件影响最大，其中最有效的中和抗体具有最短且构象最受约束的CDR3。这些结构为毒素中和的潜在机制提供了独特的见识，并为合理设计蓖麻毒素毒素亚基疫苗提供了至关重要的信息。

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