Article Figures & Data
Figures
- FIG. 1.
Structure of the sE dimer of dengue virus E sE in the mature virus particle. (A) The three domains of dengue virus sE. Domain I is red, domain II is yellow, and domain III is blue. A 53-residue stem segment links the stably folded sE fragment with the C-terminal transmembrane anchor. (B) The DEN-3 sE dimer viewed along its twofold symmetry axis. (C) The sE dimer viewed perpendicular to its twofold axis. The two glycans on residues 67 and 153 of the two subunits (A and B) of the dimer are labeled.
- FIG. 2.
Contacts involving the glycans of sE between molecules related by the crystal symmetry. A closeup of the sE dimer (in red, yellow, and blue for domains I, II, and III, respectively) viewed from the side (inset) shows that both glycans form crystal contacts with an adjacent molecule in the crystal (shown in lighter colors). Mannose residues in the glycan on Asn-153 of chain A form hydrogen bonds with the main chain and side-chain oxygen atoms of Ser-16 and the side-chain amine of Lys-36. The N-acetylglucosamine linked to Asn-67 of chain B forms a hydrogen bond with a mannose in the glycan on Asn-153 of chain B of a neighboring molecule in the crystal.
- FIG. 3.
Structure of the DEN-3 sE dimer superimposed on the DEN-2 sE dimer, using domain I from one monomer as the reference, viewed along the twofold symmetry axes (A) and perpendicular to the twofold axes (B). The greatest difference between the two structures is a ∼10° rotation of domain II relative to domain I about a point near Gly-188 (indicated by a grey star). (C) The DEN-3 sE dimer with residues that are not conserved in DEN-2 is shown in space-filling representation. Residues that are exposed on the viral surface are in magenta; residues that are not exposed are in grey. (D) The same structure as in panel C but viewed perpendicular to the twofold axis.
- FIG. 4.
Antibody neutralization-escape mutants in dengue virus. (A) Three serotype-specific epitopes have been reported: residue 291 (2), residues 301 to 307 (29), and residues 381 to 383 (17, 18). Side chains in all three epitopes are shown on the DEN-3 E structure in magenta in space-filling representation. Changes at residue 388 (in pink), also unconserved and exposed, correlate with changes in virulence (28). Phe-277 (in green) is conserved in the dengue virus serotypes, but its mutation to serine during passaging in cell culture leads to escape from neutralization by IgM M10 (2, 27). (B) A side view of panel A is shown. (C) Stereoscopic view of a close-up of DEN-3 domain III, showing the four proposed serotype-specific epitopes. The orientation is halfway between the orientations used in the models shown in panels A and B, and the close-up is of the copy of domain III shown on the right in panels A and B. (D) The same view as in panel C is shown, but of DEN-2 (and with the homologous residues highlighted).
Tables
- TABLE 1.
Crystallographic data and refinement statistics
Data set (space group) P212121 Molecules per asymmetric unit 2 Cell edges a, b, c (Å) 52.9, 68.6, 270.2 Resolution range (Å) 20-3.6 % Completenessa 92 (81) I/σ(I)a 12.3 (2.6) Rmerge (%)a 12.0 (53.8) Unique reflections 12,090 Rcrystb 0.279 Rfreec 0.324 Avg B factor (Å2) Protein (chains A and B) 73.6, 74.1 Water molecules 41.7 Rmsdd bond length (Å) 0.009 Rmsd bond angle (°) 1.532 Rmsd bonded B factor (Å2) Main chain 2.65 Side chain 3.45 Ramachandran plot (%) Favored 71.1 Allowed 28.2 Generous 0.7 Disallowed 0 - TABLE 2.
Dengue virus mutationsa
Mutation Serotype MAb Phenotype Explanation T(Q)293I DEN-1 IgM M17 More virulent and hemagglutinating at pH 5.8-7 At a hinge between domains I and III; may rigidify the hinge, requiring lower pH for conformational switch (2) K307E DEN-2 IgG G8D11 None IgG G8D11 may interfere with receptor binding (29) E311G DEN-2 IgM 6B2 None IgM 6B2 may interfere with receptor binding (32) E383G P384E/D/N G385K/S/A DEN-2 IgG 3H5 Reduced mouse neurovirulence. IgG 3H5 may interfere with receptor binding (17), probably in mosquito cells and not in human cells (18) ↵a Mutations in dengue virus that lead to escape from neutralization by monoclonal antibodies, resulting phenotypes, and possible explanations based on the structures of sE of DEN-2 and -3. Residue numbers refer to DEN-2. For unconserved residues, the residue type in DEN-2 is listed in parentheses before the residue number. Residues that are unconserved among dengue serotypes are in boldface type.
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Files in this Data Supplement:
- Supplemental file 1
-
Table S1. Mutations in dengue virus E, with potential explanations for their phenotypes, based on the structures of SE from
DEN2 and DEN3.
MS Word document, 65.5K.
- Supplemental file 1
-
Table S1. Mutations in dengue virus E, with potential explanations for their phenotypes, based on the structures of SE from
DEN2 and DEN3.
