The human γ-herpesviruses Kaposi sarcoma associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) are associated with many human malignancies. Viral glycoprotein H (gH) and glycoprotein L (gL) are crucial for the cell tropism by binding to specific receptors. Recently, EphA2 was identified as the specific entry receptor for both KSHV and EBV. Here, we characterized the crystal structures of KSHV gHgL or EBV gHgL in complex with the ligand binding domain (LBD) of EphA2. Both KSHV and EBV gHgL bind to the channel and peripheral regions of LBD primarily using gL. Extensive interactions with more contacts contribute to the higher affinity of KSHV gHgL to LBD than that of EBV gHgL. These binding characteristics were verified using cell-based fusion assays with mutations in key EphA2 residues. Our experiments suggest that multiple animal γ-herpesviruses could use EphA2 as an entry receptor, implying a potential threat to human health.

人类 γ 疱疹病毒卡波西肉瘤相关疱疹病毒 (KSHV) 和 Epstein-Barr 病毒 (EBV) 与许多人类恶性肿瘤有关。病毒糖蛋白 H (gH) 和糖蛋白 L (gL) 通过与特定受体结合对细胞嗜性至关重要。最近，EphA2 被确定为 KSHV 和 EBV 的特异性进入受体。在这里，我们表征了与 EphA2 的配体结合域 (LBD) 复合的 KSHV gHgL 或 EBV gHgL 的晶体结构。KSHV 和 EBV gHgL 都主要使用 gL 与 LBD 的通道和外围区域结合。与更多接触者的广泛相互作用导致 KSHV gHgL 对 LBD 的亲和力高于 EBV gHgL。这些结合特性使用基于细胞的融合测定法在关键 EphA2 残基中进行了验证。