KREMEN1 (KRM1) has been identified as a functional receptor for Coxsackievirus A10 (CV-A10), a causative agent of hand-foot-and-mouth disease (HFMD), which poses a great threat to infants globally. However, the underlying mechanisms for the viral entry process are not well understood. Here we determined the atomic structures of different forms of CV-A10 viral particles and its complex with KRM1 in both neutral and acidic conditions. These structures reveal that KRM1 selectively binds to the mature viral particle above the canyon of the viral protein 1 (VP1) subunit and contacts across two adjacent asymmetry units. The key residues for receptor binding are conserved among most KRM1-dependent enteroviruses, suggesting a uniform mechanism for receptor binding. Moreover, the binding of KRM1 induces the release of pocket factor, a process accelerated under acidic conditions. Further biochemical studies confirmed that receptor binding at acidic pH enabled CV-A10 virion uncoating in vitro. Taken together, these findings provide high-resolution snapshots of CV-A10 entry and identify KRM1 as a two-in-one receptor for enterovirus infection.

KREMEN1（KRM1）已被确认为柯萨奇病毒A10（CV-A10）的功能受体，柯萨奇病毒A10是手足口病（HFMD）的病原体，对全球婴儿构成巨大威胁。但是，对于病毒进入过程的基本机制还没有很好的理解。在这里，我们确定了中性和酸性条件下不同形式的CV-A10病毒颗粒的原子结构及其与KRM1的复合物。这些结构表明，KRM1选择性结合病毒蛋白1（VP1）亚基峡谷上方的成熟病毒颗粒，并跨两个相邻的不对称单元接触。在大多数KRM1依赖型肠病毒中，受体结合的关键残基是保守的，表明受体结合的统一机制。此外，KRM1的结合诱导口袋因子的释放，在酸性条件下加速的过程。进一步的生化研究证实，在酸性pH下结合受体可以使CV-A10病毒体在体外脱膜。综上所述，这些发现提供了CV-A10进入的高分辨率快照，并将KRM1识别为肠道病毒感染的二合一受体。