A potent anti-dengue human antibody preferentially recognizes the conformation of E protein monomers assembled on the virus surface

被引：139

作者：

Fibriansah, Guntur ^{[1
,2
]}

Tan, Joanne L. ^{[1
,2
]}

Smith, Scott A. ^{[3
,4
]}

de Alwis, Adamberage R. ^{[5
]}

Thiam-Seng Ng ^{[1
,2
]}

Kostyuchenko, Victor A. ^{[1
,2
]}

Ibarra, Kristie D. ^{[6
]}

Wang, Jiaqi ^{[1
,2
]}

Harris, Eva ^{[6
]}

de Silva, Aravinda

Crowe, James E., Jr. ^{[7
,8
]}

Lok, Shee-Mei ^{[1
,2
]}

机构：

[1] Duke NUS Grad Med Sch, Program Emerging Infect Dis, Singapore, Singapore

[2] Natl Univ Singapore, Ctr BioImaging Sci, Singapore 117548, Singapore

[3] Vanderbilt Univ, Dept Med, Nashville, TN USA

[4] Vanderbilt Univ, Vanderbilt Vaccine Ctr, Nashville, TN 37235 USA

[5] Univ N Carolina, Sch Med, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA

[6] Univ Calif Berkeley, Sch Publ Hlth, Div Infect Dis & Vaccinol, Berkeley, CA 94720 USA

[7] Vanderbilt Univ, Dept Pediat, Nashville, TN USA

[8] Vanderbilt Univ, Dept Pathol Microbiol & Immunol, Nashville, TN USA

来源：

EMBO MOLECULAR MEDICINE | 2014年 / 6卷 / 03期

关键词：

dengue virus; structure; neutralization; human antibody; cryoEM; WEST-NILE-VIRUS; ENVELOPE PROTEIN; MOLECULAR-DYNAMICS; MEMBRANE-FUSION; DOMAIN-III; NEUTRALIZING ANTIBODIES; CRYSTAL-STRUCTURE; RHESUS-MONKEYS; GLYCOPROTEIN; EPITOPES;

D O I：

10.1002/emmm.201303404

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Dengue virus (DENV), which consists of four serotypes (DENV1-4), infects over 400million 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 angstrom 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.

引用

页码：358 / 371

页数：14

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