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Structure of the dengue virus envelope protein after membrane fusion

Abstract

Dengue virus enters a host cell when the viral envelope glycoprotein, E, binds to a receptor and responds by conformational rearrangement to the reduced pH of an endosome. The conformational change induces fusion of viral and host-cell membranes. A three-dimensional structure of the soluble E ectodomain (sE) in its trimeric, postfusion state reveals striking differences from the dimeric, prefusion form. The elongated trimer bears three ‘fusion loops’ at one end, to insert into the host-cell membrane. Their structure allows us to model directly how these fusion loops interact with a lipid bilayer. The protein folds back on itself, directing its carboxy terminus towards the fusion loops. We propose a fusion mechanism driven by essentially irreversible conformational changes in E and facilitated by fusion-loop insertion into the outer bilayer leaflet. Specific features of the folded-back structure suggest strategies for inhibiting flavivirus entry.

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Figure 1: Structure of the dimer of dengue E soluble fragment (sE) in the mature virus particle.
Figure 2: Trimer formation and membrane insertion of dengue E protein.
Figure 3: Domain rearrangements in the dengue sE monomer during the transition to trimer.
Figure 4: The dengue sE trimer.
Figure 5: Proposed mechanism for fusion mediated by class II viral fusion proteins.

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Acknowledgements

We thank staff at BioCARS beamline 14-BM-C at the Advanced Photon Source (Argonne National Laboratory). We thank J. Zimmerberg, F. Rey and F. Heinz for discussions, and T. Walz and Y. Cheng for guidance on EM experiments. This work was supported by a long-term fellowship to Y.M. from the Human Frontier Science Program Organization, and by an NIH. grant to S.C.H., who is a Howard Hughes Medical Institute Investigator.

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Correspondence to Stephen C. Harrison.

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Modis, Y., Ogata, S., Clements, D. et al. Structure of the dengue virus envelope protein after membrane fusion. Nature 427, 313–319 (2004). https://doi.org/10.1038/nature02165

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