Structural basis of broad ebolavirus neutralization by a human survivor antibody.
Structural basis of broad ebolavirus neutralization by a human survivor antibody.
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人类幸存者抗体广泛中和埃博拉病毒的结构基础。
DOI：
10.1038/s41594-019-0191-4
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发表时间：
2019
影响因子：
16.8
通讯作者：
Dye
中科院分区：
文献类型：
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作者：
West,BrandynR;Wec,AnnaZ;Moyer,CrystalL;Fusco,MarnieL;Ilinykh,PhilippA;Huang,Kai;Wirchnianski,ArielS;James,RebekahM;Herbert,AndrewS;Hui,Sean;Goodwin,Eileen;Howell,KatieA;Kailasan,Shweta;Aman,MJavad;Walker,LauraM;Dye
目前尚不清楚内部融合环表位外的广谱中和抗埃博拉病毒抗体(Abs)的结构特征。在这里，我们描述了一种广泛中和的人类单抗(MAb)的结构，adi-15946，它是在2013年至2016年疫情的一名人类幸存者中鉴定的。AdI-15946与裂解的埃博拉病毒糖蛋白(EBOVGPCL)的晶体结构表明，单抗的结合在结构上模拟了EBOVGP核心与其糖帽β17-β18环之间的保守相互作用，从而抑制感染。EBOVgp的内体蛋白降解和mAbFVM09的结合都取代了这个环，从而增加了AdI-15946‘S保守表位的暴露，增强了中和作用。我们的工作还绘制了adi-15946的对应区，从而解释了抗苏丹病毒活性的降低，这使得合理的结构导向工程能够增强苏丹病毒的结合和中和，同时保持亲本对埃博夫病毒和本迪布乔病毒的活性。
The structural features that govern broad-spectrum activity of broadly neutralizing anti-ebolavirus antibodies (Abs) outside of the internal fusion loop epitope are currently unknown. Here we describe the structure of a broadly neutralizing human monoclonal Ab (mAb), ADI-15946, which was identified in a human survivor of the 2013–2016 outbreak. The crystal structure of ADI-15946 in complex with cleaved Ebola virus glycoprotein (EBOV GPCL) reveals that binding of the mAb structurally mimics the conserved interaction between the EBOV GP core and its glycan cap β17–β18 loop to inhibit infection. Both endosomal proteolysis of EBOV GP and binding of mAb FVM09 displace this loop, thereby increasing exposure of ADI-15946’s conserved epitope and enhancing neutralization. Our work also mapped the paratope of ADI-15946, thereby explaining reduced activity against Sudan virus, which enabled rational, structure-guided engineering to enhance binding and neutralization of Sudan virus while retaining the parental activity against EBOV and Bundibugyo virus.