The article describes the crystal structure of the soluble ectodomain of the dengue virus envelope glycoprotein (E), which is crucial for viral entry and fusion. The structure reveals a hydrophobic pocket lined by residues that influence the pH threshold for fusion. This pocket opens and closes through a conformational shift in a β-hairpin, suggesting a structural pathway for the fusion-activating transition. The presence of detergent β-OG in the crystals marks the pocket as a potential site for small-molecule inhibitors. Mutations affecting the pH threshold for fusion map to this pocket, indicating its role in the fusion process. The study provides insights into the molecular architecture and conformational changes of the dengue E protein, which could inform the development of antiviral strategies.The article describes the crystal structure of the soluble ectodomain of the dengue virus envelope glycoprotein (E), which is crucial for viral entry and fusion. The structure reveals a hydrophobic pocket lined by residues that influence the pH threshold for fusion. This pocket opens and closes through a conformational shift in a β-hairpin, suggesting a structural pathway for the fusion-activating transition. The presence of detergent β-OG in the crystals marks the pocket as a potential site for small-molecule inhibitors. Mutations affecting the pH threshold for fusion map to this pocket, indicating its role in the fusion process. The study provides insights into the molecular architecture and conformational changes of the dengue E protein, which could inform the development of antiviral strategies.