The Marburgvirus-Neutralizing Human Monoclonal Antibody MR191 Targets a Conserved Site to Block Virus Receptor Binding.
The Marburgvirus-Neutralizing Human Monoclonal Antibody MR191 Targets a Conserved Site to Block Virus Receptor Binding.
复制标题
马堡病毒中和人类单克隆抗体MR191靶向一个保守的位点，以阻止病毒受体结合。
DOI：
10.1016/j.chom.2017.12.003
复制
发表时间：
2018-01-10
影响因子：
30.3
通讯作者：
Saphire EO
中科院分区：
文献类型：
--
作者：
King LB;Fusco ML;Flyak AI;Ilinykh PA;Huang K;Gunn B;Kirchdoerfer RN;Hastie KM;Sangha AK;Meiler J;Alter G;Bukreyev A;Crowe JE Jr;Saphire EO
自从50年前首次发现马尔堡病毒以来，它已经出现了几次，在最大的暴发中有83%-90%的致死率。尽管目前还没有疫苗或治疗药物可供人类使用，但人类抗体MR191在接种致死剂量的MarburgVirus几天后对非人类灵长类动物提供了完全保护。MR191的详细中和机制仍然悬而未决。在这里，我们提出了一个3.2？晶体结构的MR191与一个三聚体马尔堡病毒表面糖蛋白(GP)的络合物。MR191通过占据保守的受体结合部位并与宿主受体Niemann-Pick C1竞争而中和。该结构照亮了GP先前无序的区域，包括茎、融合环、CX6CC开关和GP2的N-末端区域，该区域包裹在GP1的外部，以锚定MarburgVirus特异性的“翼”抗体表位。病毒逃逸突变被映射到远远超出MR191受体结合位点足迹的地方，这表明这些区域在GP四级结构中也起到了作用。使用结构分析，King等人。展示了保护性的、潜在的治疗性的单抗MR191是如何与马尔堡病毒糖蛋白受体结合部位结合的。由此产生的复合体能够在病毒中和方面胜过宿主进入受体NPC1。此外，该结构还照亮了MarburgVirus糖蛋白以前无序的功能关键区。
Since its first identification 50 years ago, Marburgviruses have emerged several times, with 83–90% lethality in the largest outbreaks. Although no vaccines or therapeutics are available for human use, the human antibody MR191 provides complete protection in nonhuman primates when delivered several days after inoculation of a lethal marburgvirus dose. The detailed neutralization mechanism of MR191 remains outstanding. Here we present a 3.2 Å crystal structure of MR191 complexed with a trimeric marburgvirus surface glycoprotein (GP). MR191 neutralizes by occupying the conserved receptor-binding site and competing with the host receptor Niemann-Pick C1. The structure illuminates previously disordered regions of GP including the stalk, fusion loop, CX6CC switch, and an N-terminal region of GP2 that wraps about the outside of GP1 to anchor a marburgvirus-specific “wing” antibody epitope. Virus escape mutations mapped far outside the MR191 receptor-binding site footprint suggest a role for these other regions in the GP quaternary structure. Using structural analysis, King et al. demonstrates how the protective, potentially therapeutic, monoclonal antibody MR191 engages the marburgvirus glycoprotein receptor-binding site. The resulting complex is able to outcompete the host entry receptor NPC1 for viral neutralization. Additionally, the structure illuminates previously disordered, functionally critical regions of the marburgvirus glycoprotein.
登录
查看更多内容
DOI：
10.1056/nejmoa1604330
发表时间：
2016-10-13
期刊：
The New England journal of medicine
影响因子：
--
作者：
PREVAIL II Writing Group;Multi-National PREVAIL II Study Team;Davey RT Jr;Dodd L;Proschan MA;Neaton J;Neuhaus Nordwall J;Koopmeiners JS;Beigel J;Tierney J;Lane HC;Fauci AS;Massaquoi MBF;Sahr F;Malvy D
通讯作者：
Malvy D
影响因子：
6.7
作者：
Fusco ML;Hashiguchi T;Cassan R;Biggins JE;Murin CD;Warfield KL;Li S;Holtsberg FW;Shulenin S;Vu H;Olinger GG;Kim DH;Whaley KJ;Zeitlin L;Ward AB;Nykiforuk C;Aman MJ;Berry JD;Saphire EO
通讯作者：
Saphire EO
影响因子：
3.7
作者：
Finn JA;Koehler Leman J;Willis JR;Cisneros A 3rd;Crowe JE Jr;Meiler J
通讯作者：
Meiler J
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
50.5
作者：
Bendandi, M.;Marillonnet, S.;Gleba, Y.
通讯作者：
Gleba, Y.