Modis Yorgo, Ogata Steven, Clements David, Harrison Stephen C
Howard Hughes Medical Institute, Children's Hospital and Harvard Medical School, 320 Longwood Avenue, Boston, Massachusetts 02115, USA.
Nature. 2004 Jan 22;427(6972):313-9. doi: 10.1038/nature02165.
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.
当病毒包膜糖蛋白E与受体结合并因内体pH值降低而发生构象重排时，登革病毒进入宿主细胞。这种构象变化诱导病毒膜与宿主细胞膜融合。处于三聚体、融合后状态的可溶性E胞外域（sE）的三维结构显示出与二聚体、融合前形式的显著差异。细长的三聚体一端有三个“融合环”，可插入宿主细胞膜。它们的结构使我们能够直接模拟这些融合环如何与脂质双层相互作用。蛋白质自身折叠，将其羧基末端指向融合环。我们提出了一种由E中基本不可逆的构象变化驱动、并由融合环插入外双层小叶促进的融合机制。折叠后结构的特定特征提示了抑制黄病毒进入的策略。
