A shared structural solution for neutralizing ebolaviruses

Abstract

Sudan virus (genus Ebolavirus) is lethal, yet no monoclonal antibody is known to neutralize it. We here describe antibody 16F6 that neutralizes Sudan virus and present its structure bound to the trimeric viral glycoprotein. Unexpectedly, the 16F6 epitope overlaps that of KZ52, the only other antibody against the GP(1,2) core to be visualized to date. Furthermore, both antibodies against this crucial epitope bridging GP1-GP2 neutralize at a post-internalization step--probably fusion.

Figure 1

Structure of Sudan virus (SUDV) GP_1,2 in complex with Fab 16F6. GP1 subunits are colored three different shades of green, GP2 subunits are white, and bound 16F6 Fab fragments are gold. (a) Side view with viral membrane toward bottom and target cell toward the top. Note that 16F6 binds the base of the GP_1,2 peplomer, distal from putative receptor-binding sites. (b) Top view, from the perspective of the target cell. Putative receptor-binding sites are indicated by pink circles. (c) Superposition of the SUDV and Ebola virus (EBOV) GP_1,2 monomers. SUDV GP1–GP2 is colored green for GP1 and white for GP2, while EBOV GP1–GP2 is colored blue for GP1 and yellow for GP2. The SUDV structure includes additional regions of the glycan cap (top), the linker between heptad repeats 1 and 2 (HR1 and HR2) and the CX6CC motif (bottom), although the N terminus of GP2 is disordered. (d) The linker region between HR1 and HR2 forms two disulfide bonds per monomer: one linking GP1 to GP2 (Cys 53-Cys 609) and one within GP2 (Cys 601-Cys 608). All Figures have been generated with PyMOL and VMD.

Figure 2

Surfaces of SUDV GP. (a) Sequence conservation. Residues that are identical between SUDV and EBOV are colored red, while these that are different are colored yellow. The domains of one GP_1,2 monomer are outlined in black with subdomains indicated. (b) Electrostatic potential representation of the SUDV GP_1,2 surface with limits +/− 10 keT. (c) Electrostatic potential representation of the EBOV GP_1,2 surface with limits +/− 10 keT.

Figure 3

16F6 epitope. (a) mAbs 16F6 and KZ52 recognize similar GP1–GP2-bridging epitopes (black oval). Here, the structure of SUDV GP_1,2 in complex with 16F6 (gold) is superimposed with the structure of EBOV GP_1,2 in complex with KZ52 (brick red). Only the SUDV GP_1,2 trimer (green and white) is shown for clarity. (b) Epitope footprints of 16F6 (yellow) and KZ52 (red) are mapped onto the SUDV surface, for which a single GP_1,2 monomer is shown in green for GP1 and white for GP2. Residues shared between the two antibody epitopes (T42, L43, E44, P513, N550, Q551, N552, A553 and C556) are colored orange.