Structure of EBOV and MARV glycoproteins and mutational analysis of tyrosine 517 reveals a MARV-like phenotype.

(A) Domain schematic of the EBOV and MARV GP and amino acid sequence homology between EBOV and MARV. Domains are numbered according to the crystal structure. Homology was determined using sequence alignment software (Geneious Prime 2019.2.1); (B) Co-crystal structure of Ebola virus (Zaire) glycoprotein complexed with toremifene (outlined by blue box, PDB: 5JQ7); (C) Overlay of the Ebola virus glycoprotein (white) with the Ravn virus glycoprotein (green, PDB: 6BP2) reveals an α-helix (α2) in marburgviruses that could block the drug-binding cavity (blue box); (D) The position of Tyrosine 517 (side chain is marked in light blue) in the fusion loop-associated binding pocket and estimated distances for π-π interactions with aromatic rings of Toremifene (distances for phenyl rings A, B, and C are 5.7 Å, 5.4 Å, and 5.4 Å, respectively); (E) Dose-response curves for toremifene against pseudotyped WT-EBOV, WT-MARV, and EBOV mutants Y517S, Y517I, and Y517F. Disruption of π-π interactions between EBOV Tyrosine 517 and toremifene produce a MARV-like dose-response curve. All error bars represent s.d. from three independent experiments.