Structure of trimeric pre-fusion rabies virus glycoprotein in complex with two protective antibodies.
Structure of trimeric pre-fusion rabies virus glycoprotein in complex with two protective antibodies.
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DOI：
10.1016/j.chom.2022.07.014
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发表时间：
2022-09-14
影响因子：
30.3
通讯作者：
Douglas, Alexander D.
中科院分区：
文献类型：
--
作者：
Ng, Weng M.;Fedosyuk, Sofiya;English, Solomon;Augusto, Gilles;Berg, Adam;Thorley, Luke;Haselon, Anna-Sophie;Segireddy, Rameswara R.;Bowden, Thomas A.;Douglas, Alexander D.
狂犬病病毒 (RABV) 会引起致命性脑炎，每年导致约 60,000 人死亡。作为唯一的病毒颗粒表面蛋白，狂犬病病毒糖蛋白（RABV-G）介导宿主细胞进入。 RABV-G 的融合前三聚体构象显示出与保护性中和抗体结合的表位，这些表位可以通过疫苗接种诱导或被动给药以进行暴露后预防。我们报告了融合前构象的 RABV-G 三聚体的 2.8-Å 结构，与识别不同表位的两种中和和保护性单克隆抗体 17C7 和 1112-1 形成复合物。其中一种抗体是获得许可的预防剂（17C7，Rabishield），我们证明它可以将蛋白质锁定在融合前构象。靶向突变同样可以将 RABV-G 稳定在融合前构象，这是结构引导疫苗设计的关键一步。这些数据揭示了关键治疗靶点的高阶结构以及结合两个关键抗原位点的抗体中和的结构基础，这将有助于改进疫苗和预防性抗体的开发。三聚体融合前狂犬病病毒糖蛋白的 2.8-Å 冷冻电镜结构揭示了三聚化界面和两种中和抗体的结合构象转变可以被抗体和靶向突变抑制 Ng，Fedosyuk 等人。展示了融合前三聚体狂犬病糖蛋白（RABV-G）与两种中和抗体的复合物的结构，其中一种（17C7）在临床上用于暴露后预防。他们表明 17C7 抑制融合前到融合后的构象转变，并且他们鉴定出具有类似效果的氨基酸取代。
Rabies virus (RABV) causes lethal encephalitis and is responsible for approximately 60,000 deaths per year. As the sole virion-surface protein, the rabies virus glycoprotein (RABV-G) mediates host-cell entry. RABV-G’s pre-fusion trimeric conformation displays epitopes bound by protective neutralizing antibodies that can be induced by vaccination or passively administered for post-exposure prophylaxis. We report a 2.8-Å structure of a RABV-G trimer in the pre-fusion conformation, in complex with two neutralizing and protective monoclonal antibodies, 17C7 and 1112-1, that recognize distinct epitopes. One of these antibodies is a licensed prophylactic (17C7, Rabishield), which we show locks the protein in pre-fusion conformation. Targeted mutations can similarly stabilize RABV-G in the pre-fusion conformation, a key step toward structure-guided vaccine design. These data reveal the higher-order architecture of a key therapeutic target and the structural basis of neutralization by antibodies binding two key antigenic sites, and this will facilitate the development of improved vaccines and prophylactic antibodies. 2.8-Å cryo-EM structure of trimeric pre-fusion rabies virus glycoprotein Structure reveals trimerization interface and binding of two neutralizing antibodies Conformational transition can be inhibited by both antibodies and targeted mutation Ng, Fedosyuk et al. present the structure of a complex of pre-fusion trimeric rabies glycoprotein (RABV-G) with two neutralizing antibodies, one of which (17C7) is used clinically for post-exposure prophylaxis. They show that 17C7 inhibits pre- to post-fusion conformational transition, and they identify amino acid substitutions with a similar effect.
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影响因子：
3.7
作者：
Gaudin Y;Ruigrok RW;Tuffereau C;Knossow M;Flamand A
通讯作者：
Flamand A
影响因子：
3.8
作者：
Hampson K;Coudeville L;Lembo T;Sambo M;Kieffer A;Attlan M;Barrat J;Blanton JD;Briggs DJ;Cleaveland S;Costa P;Freuling CM;Hiby E;Knopf L;Leanes F;Meslin FX;Metlin A;Miranda ME;Müller T;Nel LH;Recuenco S;Rupprecht CE;Schumacher C;Taylor L;Vigilato MA;Zinsstag J;Dushoff J;Global Alliance for Rabies Control Partners for Rabies Prevention
通讯作者：
Global Alliance for Rabies Control Partners for Rabies Prevention
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
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通讯作者：
Cowtan, K
影响因子：
11.4
作者：
Baquero, Eduard;Albertini, Aurelie A.;Gaudin, Yves
通讯作者：
Gaudin, Yves
影响因子：
5.5
作者：
Aldrich C;Leroux-Roels I;Huang KB;Bica MA;Loeliger E;Schoenborn-Kellenberger O;Walz L;Leroux-Roels G;von Sonnenburg F;Oostvogels L
通讯作者：
Oostvogels L