dc.contributor.authorWong, Yee Hwa
dc.contributor.authorKumar, Akshita
dc.contributor.authorLiew, Chong Wai
dc.contributor.authorTharakaraman, Kannan
dc.contributor.authorSrinivasaraghavan, Kannan
dc.contributor.authorSasisekharan, Ram
dc.contributor.authorVerma, Chandra
dc.contributor.authorLescar, Julien
dc.identifier.citationWong, Y. H., Kumar, A., Liew, C. W., Tharakaraman, K., Srinivasaraghavan, K., Sasisekharan, R., et al. (2018). Molecular basis for dengue virus broad cross-neutralization by humanized monoclonal antibody 513. Scientific Reports, 8(1), 8449-.en_US
dc.description.abstractDengue 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.en_US
dc.description.sponsorshipNRF (Natl Research Foundation, S’pore)en_US
dc.format.extent17 p.en_US
dc.relation.ispartofseriesScientific Reportsen_US
dc.rights© 2018 The Author(s) (Nature Publishing Group). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.en_US
dc.subjectDengue Virusen_US
dc.subjectHumanized Monoclonal Antibody 513en_US
dc.titleMolecular basis for dengue virus broad cross-neutralization by humanized monoclonal antibody 513en_US
dc.typeJournal Article
dc.contributor.researchNTU Institute of Structural Biologyen_US
dc.contributor.schoolSchool of Biological Sciencesen_US
dc.description.versionPublished versionen_US

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