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Potent Dengue Virus Neutralization by a Therapeutic Antibody with Low Monovalent Affinity Requires Bivalent Engagement

Figure 6

Modeling of E106 binding to DENV.

(A) The E106 epitope is highlighted in magenta on a DENV-1 model of the DENV-2 cryo-electron microscopic reconstruction (PDB code 1P58). All atoms of the model are displayed and colored by domains (DI, red; DII, gold; DIII, blue). Magnified view of the boxed region in (A) with E106 Fab docked onto the epitopes at the primary candidates for bivalent antibody binding namely (B) adjacent 2-fold epitopes (49 ƅ CH1 separation) which is permuted as an outer 5-fold ring and (C) adjacent inner and outer 5-fold epitopes (24 ƅ CH1 separation). E106 Fab heavy and light chain is represented by green and cyan spheres, respectively. The C-terminal CH1 residue is represented by ā€˜Cā€™. (D) Schematic of the possible arrangements of E106 MAb bivalent binding to the lateral ridge plus A-strand epitope (magenta) on a single virion. The distances labeled in magenta and green are E106 epitope (T329) and C-terminal CH1 residue (R214) distances respectively. One Fab pair (green, heavy chain; cyan, light chain) is shown across the 5- and 2-fold and another involves adjacent 2-fold symmetry axes (the 2-fold permutes as an outer 5-fold ring, dashed gray line). 5-, 3- and 2-fold axes of symmetry are connected by gray dashed lines for clarity and represented by pentagons, triangles, and ovals, respectively. Epitopes that are occluded as a result of bivalent binding are shown in gray.

Figure 6

doi: https://doi.org/10.1371/journal.ppat.1004072.g006