1. Howard Hughes Medical Institute, Children's Hospital and Harvard Medical School, 320 Longwood Avenue, Boston, Massachusetts 02115, USA
2. Hawaii Biotech, Inc., 99–193 Aiea Heights Drive, Suite 200, Aiea, Hawaii, Hawaii 96701, USA

Correspondence to: Stephen C. Harrison¹ Email: harrison@crystal.harvard.edu
Coordinates have been deposited in the Protein Data Bank under accession code 1OK8.

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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