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. 2017 Mar 16:8:14722.
doi: 10.1038/ncomms14722.

A human antibody against Zika virus crosslinks the E protein to prevent infection

Affiliations

A human antibody against Zika virus crosslinks the E protein to prevent infection

S Saif Hasan et al. Nat Commun. .

Abstract

The recent Zika virus (ZIKV) epidemic has been linked to unusual and severe clinical manifestations including microcephaly in fetuses of infected pregnant women and Guillian-Barré syndrome in adults. Neutralizing antibodies present a possible therapeutic approach to prevent and control ZIKV infection. Here we present a 6.2 Å resolution three-dimensional cryo-electron microscopy (cryoEM) structure of an infectious ZIKV (strain H/PF/2013, French Polynesia) in complex with the Fab fragment of a highly therapeutic and neutralizing human monoclonal antibody, ZIKV-117. The antibody had been shown to prevent fetal infection and demise in mice. The structure shows that ZIKV-117 Fabs cross-link the monomers within the surface E glycoprotein dimers as well as between neighbouring dimers, thus preventing the reorganization of E protein monomers into fusogenic trimers in the acidic environment of endosomes.

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Conflict of interest statement

M.S.D. is a consultant for Inbios and Visterra, on the Scientific Advisory Boards of Moderna and OraGene, and a recipient of grants from Moderna and Visterra. J.E.C. is a consultant for Sanofi and Ridgeback Biotherapeutics, is on the Scientific Advisory Boards of PaxVax, CompuVax, GigaGen, Meissa Vaccines and is a recipient of research grants from Moderna and Sanofi. The remaining authors declare no competing financial interests.

Figures

Figure 1
Figure 1. CryoEM map of ZIKV/ZIKV-117.
The ZIKV-Fab surface is shown in radial colouring, from yellow (∼210 Å) to red (∼290 Å). The bound Fab (red ‘knobs') extends from the surface of ZIKV, which is shown in yellow. The Fab sites close to the two-fold (‘2f'), three-fold (‘3f') and five-fold (‘5f') axes are labelled. The icosahedral 2 (oval), 3 (triangle) and 5 (pentagon) fold axes are marked in blue shapes with black outlines, and a representative asymmetric unit is shown as a black triangle.
Figure 2
Figure 2. Fab binding sites on ZIKV surface.
The E proteins are represented in three colours—blue (chains A, A′ and A′′), red (chains C, C′ and C′′) and green (chains E, E′ and E′′). Chains A and A′ are arranged in a dimer around the icosahedral two-fold axis (blue oval with black outline), while chains C and E are arranged in a general dimer around a quasi two-fold axis (yellow oval with black outline). The icosahedral and general dimers are related by an axis of quasi two-fold symmetry (orange oval with black outline). Residues Asp67 (red), Gln89 (green) and Lys118 (blue), which were mapped to the Fab binding site by mutagenesis, are shown as spheres. The footprints of the Fab bound at the 2f and 3f sites are represented as light and dark grey ovals with broken outlines. The black stars mark the position of the fusion peptides. The steric hindrance on the 5f site due to the orientation of DIII of chain A′′ is highlighted by black arrows. For reference, two asymmetric units are shown as triangles in solid and broken dashed lines. The icosahedral five- and three-fold axes are marked with a pentagon and two triangles receptively.
Figure 3
Figure 3. Footprints of ZIKV-117 Fabs on the E protein.
The figure shows a roadmap of the ZIKV E protein. The E protein residues are coloured according to their distance from the virus centre, with the residues closer to the centre coloured blue (218 Å) and those farthest from the centre coloured red (235 Å). The colours of residues transition from blue to red through green. The position of the icosahedral two-fold axis is marked with a blue oval. The quasi two-fold axes are marked as orange or yellow ovals. The outlines of the individual E protein chains are marked with thick black lines, and the chains are labelled as per the convention described in Fig. 2. The residues Asp67, Gln89 and Lys118 within the ZIKV-117 epitope are highlighted with red lines. The ZIKV-117 footprints formed by E protein residues that lie within 8 Å of the bound Fab at the 2f (yellow outline) and 3f (white outline) sites are highlighted across the quasi two-fold axis (orange oval). The footprints extend across multiple E proteins, and there is significant overlap between the footprints. At the 5f site, DIII of chain A′′ (highlighted with a white arrow) poses a steric barrier to the binding of Fab.

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