Hepatitis C virus (HCV) infection is a causal agent of chronic liver disease, cirrhosis and hepatocellular carcinoma in humans, and afflicts more than 70 million people worldwide. The HCV envelope glycoproteins E1 and E2 are responsible for the binding of the virus to the host cell, but the exact entry process remains undetermined¹. The majority of broadly neutralizing antibodies block interaction between HCV E2 and the large extracellular loop (LEL) of the cellular receptor CD81 (CD81-LEL)². Here we show that low pH enhances the binding of CD81-LEL to E2, and we determine the crystal structure of E2 in complex with an antigen-binding fragment (2A12) and CD81-LEL (E2–2A12–CD81-LEL); E2 in complex with 2A12 (E2–2A12); and CD81-LEL alone. After binding CD81, residues 418–422 in E2 are displaced, which allows for the extension of an internal loop consisting of residues 520–539. Docking of the E2–CD81-LEL complex onto a membrane-embedded, full-length CD81 places the residues Tyr529 and Trp531 of E2 proximal to the membrane. Liposome flotation assays show that low pH and CD81-LEL increase the interaction of E2 with membranes, whereas structure-based mutants of Tyr529, Trp531 and Ile422 in the amino terminus of E2 abolish membrane binding. These data support a model in which acidification and receptor binding result in a conformational change in E2 in preparation for membrane fusion.

丙型肝炎病毒 (HCV) 感染是人类慢性肝病、肝硬化和肝细胞癌的病原体，全世界有超过 7000 万人受其折磨。HCV 包膜糖蛋白 E1 和 E2 负责病毒与宿主细胞的结合，但确切的进入过程仍未确定¹。大多数广泛中和抗体阻断 HCV E2 与细胞受体 CD81 (CD81-LEL) ^{2的大细胞外环 (LEL) 之间的相互作用}. 在这里，我们表明低 pH 值增强了 CD81-LEL 与 E2 的结合，并且我们确定了 E2 与抗原结合片段 (2A12) 和 CD81-LEL (E2–2A12–CD81-LEL) 复合物的晶体结构；E2 与 2A12 复合 (E2–2A12)；和单独的 CD81-LEL。结合 CD81 后，E2 中的残基 418-422 被置换，这允许延伸由残基 520-539 组成的内部环。将 E2–CD81-LEL 复合物对接到膜包埋的全长 CD81 上，将 E2 的残基 Tyr529 和 Trp531 置于膜附近。脂质体浮选测定显示低 pH 和 CD81-LEL 增加了 E2 与膜的相互作用，而 E2 氨基末端的基于结构的 Tyr529、Trp531 和 Ile422 突变体消除了膜结合。