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Cryo-EM structures of anti-malarial antibody L9 with circumsporozoite protein reveal trimeric L9 association and complete 27-residue epitope
Structure ( IF 4.4 ) Pub Date : 2023-03-16 , DOI: 10.1016/j.str.2023.02.009
Prabhanshu Tripathi 1 , Michael F Bender 1 , Haotian Lei 2 , Lais Da Silva Pereira 1 , Chen-Hsiang Shen 1 , Brian Bonilla 1 , Marlon Dillon 1 , Li Ou 1 , Marie Pancera 3 , Lawrence T Wang 1 , Baoshan Zhang 1 , Facundo D Batista 4 , Azza H Idris 1 , Robert A Seder 1 , Peter D Kwong 1
Affiliation  

Monoclonal antibody L9 recognizes the Plasmodium falciparum circumsporozoite protein (PfCSP) and is highly protective following controlled human malaria challenge. To gain insight into its function, we determined cryoelectron microscopy (cryo-EM) structures of L9 in complex with full-length PfCSP and assessed how this recognition influenced protection by wild-type and mutant L9s. Cryo-EM reconstructions at 3.6- and 3.7-Å resolution revealed L9 to recognize PfCSP as an atypical trimer. Each of the three L9s in the trimer directly recognized an Asn-Pro-Asn-Val (NPNV) tetrapeptide on PfCSP and interacted homotypically to facilitate L9-trimer assembly. We analyzed peptides containing different repeat tetrapeptides for binding to wild-type and mutant L9s to delineate epitope and homotypic components of L9 recognition; we found both components necessary for potent malaria protection. Last, we found the 27-residue stretch recognized by L9 to be highly conserved in P. falciparum isolates, suggesting the newly revealed complete L9 epitope to be an attractive vaccine target.



中文翻译:


抗疟疾抗体 L9 与环子孢子蛋白的冷冻电镜结构揭示了三聚体 L9 关联和完整的 27 个残基表位



单克隆抗体 L9 可识别恶性疟原虫环子孢子蛋白 (PfCSP),并且在受控的人类疟疾攻击后具有高度保护性。为了深入了解其功能,我们确定了 L9 与全长 PfCSP 复合物的冷冻电子显微镜 (cryo-EM) 结构,并评估了这种识别如何影响野生型和突变型 L9 的保护作用。 3.6 和 3.7 Å 分辨率的冷冻电镜重建显示 L9 将 PfCSP 识别为非典型三聚体。三聚体中的三个 L9 均直接识别 PfCSP 上的 Asn-Pro-Asn-Val (NPNV) 四肽,并同型相互作用以促进 L9 三聚体组装。我们分析了含有不同重复四肽的肽与野生型和突变型 L9 的结合,以描绘 L9 识别的表位和同型成分;我们发现这两种成分都是有效预防疟疾所必需的。最后,我们发现 L9 识别的 27 个残基序列在恶性疟原虫分离株中高度保守,这表明新发现的完整 L9 表位是一个有吸引力的疫苗靶点。

更新日期:2023-03-16
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