The Dengue virus (DENV) envelope (E) protein is the major component of the viral surface and is structurally subdivided into three domains, ED1, ED2 and ED3. ED3 elicits potent neutralizing antibodies and contains two major antigenic sites: The DENV-type-specific and DENV-complex-reactive antigenic sites. Each site is composed of a limited subset of residues that are required for monoclonal antibody (mAb) binding. Here we show that DENV-2-type-specific mAb 9A3D-8 utilizes the functionally critical residues K307, V308, K310, I312, P332, L387, L389 and N390 for ED3 binding. Surprisingly, this DENV- type-specific epitope is predicted to overlap with the ED3 DENV-complex-reactive antigenic site on the viral surface. Further, this unique binding site enables mAb 9A3D-8 to neutralize virus infectivity at relatively low occupancy of virions compared to other ED3 mAbs identified to date. Together, the data in this study indicate that this is a new DENV-2-type-specific antigenic site on ED3.
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