Please use this identifier to cite or link to this item: https://doi.org/10.1038/s41598-018-26800-y
Title: Molecular basis for dengue virus broad cross-neutralization by humanized monoclonal antibody
Authors: Wong, Y.H
Kumar, A
Liew, C.W
Tharakaraman, K
Srinivasaraghavan, K
Sasisekharan, R
Verma, C 
Lescar, J 
Keywords: epitope
monoclonal antibody
single chain fragment variable antibody
virus envelope protein
amino acid sequence
animal
antigen antibody complex
binding site
calorimetry
chemistry
classification
cross reaction
dengue
Dengue virus
genetics
human
immunology
molecular dynamics
mouse
pathology
protein tertiary structure
sequence alignment
serodiagnosis
serotype
virology
Amino Acid Sequence
Animals
Antibodies, Monoclonal, Humanized
Antigen-Antibody Complex
Binding Sites
Calorimetry
Cross Reactions
Dengue
Dengue Virus
Epitopes
Humans
Mice
Molecular Dynamics Simulation
Neutralization Tests
Protein Structure, Tertiary
Sequence Alignment
Serogroup
Single-Chain Antibodies
Viral Envelope Proteins
Issue Date: 2018
Citation: Wong, Y.H, Kumar, A, Liew, C.W, Tharakaraman, K, Srinivasaraghavan, K, Sasisekharan, R, Verma, C, Lescar, J (2018). Molecular basis for dengue virus broad cross-neutralization by humanized monoclonal antibody. Scientific Reports 8 (1) : 8449. ScholarBank@NUS Repository. https://doi.org/10.1038/s41598-018-26800-y
Rights: Attribution 4.0 International
Abstract: Dengue is a widespread viral disease with 3.6 billion people at risk worldwide. Humanized monoclonal antibody (mAb) 513, currently undergoing clinical trials in Singapore, targets an epitope on the envelope protein domain III exposed at the surface of the viral particle. This antibody potently neutralizes all four dengue virus serotypes in a humanized mouse model that recapitulates human dengue infection, without signs of antibody-mediated enhancement of the disease. The crystal structure of single-chain variable fragment (scFv) 513 bound to the envelope protein domain III from dengue virus serotype 4 was used as a template to explore the molecular origins of the broader cross-reactivity and increased in vivo potency of mAb 513, compared to the parent murine mAb 4E11, using molecular dynamics simulations and network analyses. These two methods are a powerful complement to existing structural and binding data and detail specific interactions that underpin the differential binding of the two antibodies. We found that a Glu at position H55 (GluH55) from the second Complementarity Determining Region of the Heavy chain (CDR-H2) which corresponds to Ala in 4E11, is a major contributor to the enhancement in the interactions of mAb 513 compared to 4E11. Importantly, we also validate the importance of GluH55 using site-directed mutagenesis followed by isothermal titration calorimetry measurements. © 2018 The Author(s).
Source Title: Scientific Reports
URI: https://scholarbank.nus.edu.sg/handle/10635/177818
ISSN: 20452322
DOI: 10.1038/s41598-018-26800-y
Rights: Attribution 4.0 International
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