A potent anti-dengue human antibody preferentially recognizes the conformation of E protein monomers assembled on the virus surface.
A potent anti-dengue human antibody preferentially recognizes the conformation of E protein monomers assembled on the virus surface.
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DOI：
10.1002/emmm.201303404
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发表时间：
2014-03
影响因子：
11.1
通讯作者：
Lok, Shee-Mei
中科院分区：
文献类型：
--
作者：
Fibriansah, Guntur;Tan, Joanne L.;Smith, Scott A.;de Alwis, Adamberage R.;Thiam-Seng Ng;Kostyuchenko, Victor A.;Ibarra, Kristie D.;Wang, Jiaqi;Harris, Eva;de Silva, Aravinda;Crowe, James E., Jr.;Lok, Shee-Mei
登革病毒（DENV）由四种血清型（DENV1 - 4）组成，每年感染超过4亿人。先前的研究表明，来自登革热患者的大多数人单克隆抗体（HMAb）具有交叉反应性且中和能力差。罕见的中和性HMAb通常具有血清型特异性，并结合依赖于四级结构的表位。我们通过冷冻电镜技术确定了登革病毒1型与一种高效HMAb 1F4的Fab片段形成的复合物结构，分辨率达到6 Å。尽管在先前的研究中，酶联免疫吸附测定（ELISA）显示HMAb 1F4似乎与病毒结合而非与E蛋白结合，但我们的结构表明该表位位于包膜（E）蛋白单体内部，而非跨越相邻的E蛋白。Fab分子结合到E蛋白的结构域I（DI）以及DI - DII铰链区域。我们还表明，HMAb 1F4能够以一种依赖细胞类型和受体的方式在病毒进入细胞的不同阶段中和登革病毒1型。该结构揭示了这种高效且特异性的抗体阻断病毒感染的机制。
学科分类：微生物学、病毒学与宿主 - 病原体相互作用；免疫学
Dengue virus (DENV), which consists of four serotypes (DENV1-4), infects over 400 million people annually. Previous studies have indicated most human monoclonal antibodies (HMAbs) from dengue patients are cross-reactive and poorly neutralizing. Rare neutralizing HMAbs are usually serotype-specific and bind to quaternary structure-dependent epitopes. We determined the structure of DENV1 complexed with Fab fragments of a highly potent HMAb 1F4 to 6 Å resolution by cryo-EM. Although HMAb 1F4 appeared to bind to virus and not E proteins in ELISAs in the previous study, our structure showed that the epitope is located within an envelope (E) protein monomer, and not across neighboring E proteins. The Fab molecules bind to domain I (DI), and DI-DII hinge of the E protein. We also showed that HMAb 1F4 can neutralize DENV at different stages of viral entry in a cell type and receptor dependent manner. The structure reveals the mechanism by which this potent and specific antibody blocks viral infection. Subject Categories Microbiology, Virology & Host Pathogen Interaction; Immunology
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影响因子：
6.7
作者：
Balsitis SJ;Williams KL;Lachica R;Flores D;Kyle JL;Mehlhop E;Johnson S;Diamond MS;Beatty PR;Harris E
通讯作者：
Harris E
影响因子：
6.7
作者：
Austin SK;Dowd KA;Shrestha B;Nelson CA;Edeling MA;Johnson S;Pierson TC;Diamond MS;Fremont DH
通讯作者：
Fremont DH
影响因子：
11.4
作者：
Cockburn, Joseph J. B.;Sanchez, M. Erika Navarro;Rey, Felix A.
通讯作者：
Rey, Felix A.
影响因子：
30.3
作者：
Beltramello M;Williams KL;Simmons CP;Macagno A;Simonelli L;Quyen NT;Sukupolvi-Petty S;Navarro-Sanchez E;Young PR;de Silva AM;Rey FA;Varani L;Whitehead SS;Diamond MS;Harris E;Lanzavecchia A;Sallusto F
通讯作者：
Sallusto F
影响因子：
2.2
作者：
Imrie, Allison;Meeks, Janet;Effler, Paul
通讯作者：
Effler, Paul