ZMapp, a cocktail of three monoclonal antibodies (MAbs; c2G4, c4G7, and c13C6) 
against the ebolavirus (EBOV) glycoprotein (GP), shows promise for combatting 
outbreaks of EBOV, as occurred in West Africa in 2014. Prior studies showed that 
Fabs from these MAbs bind a soluble EBOV GP ectodomain and that MAbs c2G4 and 
c4G7, but not c13C6, neutralize infections in cell cultures. Using cryo-electron 
tomography, we extended these findings by characterizing the structures of c2G4, 
c4G7, and c13C6 IgGs bound to native, full-length GP from the West African 2014 
isolate embedded in filamentous viruslike particles (VLPs). As with the isolated 
ectodomain, c13C6 bound to the glycan cap, whereas c2G4 and c4G7 bound to the 
base region of membrane-bound GP. The tomographic data suggest that all three 
MAbs bind with high occupancy and that the base-binding antibodies can 
potentially bridge neighboring GP spikes. Functional studies indicated that c2G4 
and c4G7, but not c13C6, competitively inhibit entry of VLPs bearing EBOV GP 
into the host cell cytoplasm, without blocking trafficking of VLPs to NPC1(+) 
endolysosomes, where EBOV fuses. Moreover, c2G4 and c4G7 bind to and can block 
entry mediated by the primed (19-kDa) form of GP without impeding binding of the 
C-loop of NPC1, the endolysosomal receptor for EBOV. The most likely mode of 
action of c2G4 and c4G7 is therefore by inhibiting conformational changes in 
primed, NPC1-bound GP that initiate fusion between the viral and target 
membranes, similar to the action of certain broadly neutralizing antibodies 
against influenza hemagglutinin and HIV Env.
IMPORTANCE: The recent West African outbreak of ebolavirus caused the deaths of 
more than 11,000 individuals. Hence, there is an urgent need to be prepared with 
vaccines and therapeutics for similar future disasters. ZMapp, a cocktail of 
three MAbs directed against the ebolavirus glycoprotein, is a promising 
anti-ebolavirus therapeutic. Using cryo-electron tomography, we provide 
structural information on how each of the MAbs in this cocktail binds to the 
ebolavirus glycoprotein as it is displayed-embedded in the membrane and present 
at high density-on filamentous viruslike particles that recapitulate the surface 
structure and entry functions of ebolavirus. Moreover, after confirming that two 
of the MAbs bind to the same region in the base of the glycoprotein, we show 
that they competitively block the entry function of the glycoprotein and that 
they can do so after the glycoprotein is proteolytically primed and bound to its 
intracellular receptor, Niemann-Pick C1. These findings should inform future 
developments of ebolavirus therapeutics.