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1.
Nat Commun ; 13(1): 6756, 2022 11 09.
Article in English | MEDLINE | ID: mdl-36347841

ABSTRACT

Dengue virus infection can cause dengue hemorrhagic fever (DHF). Dengue NS1 is multifunctional. The intracellular dimeric NS1 (iNS1) forms part of the viral replication complex. Previous studies suggest the extracellular secreted NS1 (sNS1), which is a major factor contributing to DHF, exists as hexamers. The structure of the iNS1 is well-characterised but not that of sNS1. Here we show by cryoEM that the recombinant sNS1 exists in multiple oligomeric states: the tetrameric (stable and loose conformation) and hexameric structures. Stability of the stable and loose tetramers is determined by the conformation of their N-terminal domain - elongated ß-sheet or ß-roll. Binding of an anti-NS1 Fab breaks the loose tetrameric and hexameric sNS1 into dimers, whereas the stable tetramer remains largely unbound. Our results show detailed quaternary organization of different oligomeric states of sNS1 and will contribute towards the design of dengue therapeutics.


Subject(s)
Dengue Virus , Dengue , Noonan Syndrome , Severe Dengue , Humans , Dengue Virus/metabolism , Viral Nonstructural Proteins/chemistry
2.
Cell ; 184(25): 6067-6080.e13, 2021 12 09.
Article in English | MEDLINE | ID: mdl-34852238

ABSTRACT

The human monoclonal antibody (HmAb) C10 potently cross-neutralizes Zika virus (ZIKV) and dengue virus. Analysis of antibody fragment (Fab) C10 interactions with ZIKV and dengue virus serotype 2 (DENV2) particles by cryoelectron microscopy (cryo-EM) and amide hydrogen/deuterium exchange mass spectrometry (HDXMS) shows that Fab C10 binding decreases overall ZIKV particle dynamics, whereas with DENV2, the same Fab causes increased dynamics. Testing of different Fab C10:DENV2 E protein molar ratios revealed that, at higher Fab ratios, especially at saturated concentrations, the Fab enhanced viral dynamics (detected by HDXMS), and observation under cryo-EM showed increased numbers of distorted particles. Our results suggest that Fab C10 stabilizes ZIKV but that with DENV2 particles, high Fab C10 occupancy promotes E protein dimer conformational changes leading to overall increased particle dynamics and distortion of the viral surface. This is the first instance of a broadly neutralizing antibody eliciting virus-specific increases in whole virus particle dynamics.


Subject(s)
Antibodies, Neutralizing , Dengue Virus , Dengue , Viral Envelope Proteins , Zika Virus Infection , Zika Virus , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/metabolism , Antibodies, Viral/immunology , Cross Reactions , Dengue/immunology , Dengue/virology , Dengue Virus/immunology , Dengue Virus/physiology , Humans , Protein Binding , Viral Envelope Proteins/chemistry , Viral Envelope Proteins/immunology , Viral Envelope Proteins/metabolism , Zika Virus/immunology , Zika Virus/physiology , Zika Virus Infection/immunology , Zika Virus Infection/virology
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