The human monoclonal antibody C10 exhibits extraordinary cross-reactivity, potently neutralizing Zika virus (ZIKV) and the four serotypes of dengue virus (DENV1–DENV4). Here we describe a comparative structure-function analysis of C10 bound to the envelope (E) protein dimers of the five viruses it neutralizes. We demonstrate that the C10 Fab has high affinity for ZIKV and DENV1 but not for DENV2, DENV3, and DENV4. We further show that the C10 interaction with the latter viruses requires an E protein conformational landscape that limits binding to only one of the three independent epitopes per virion. This limited affinity is nevertheless counterbalanced by the particle’s icosahedral organization, which allows two different dimers to be reached by both Fab arms of a C10 immunoglobulin. The epitopes’ geometric distribution thus confers C10 its exceptional neutralization breadth. Our results highlight the importance not only of paratope/epitope complementarity but also the topological distribution for epitope-focused vaccine design.

人单克隆抗体 C10 表现出非凡的交叉反应性，可有效中和寨卡病毒 (ZIKV) 和四种血清型登革热病毒 (DENV1–DENV4)。在这里，我们描述了 C10 与其中和的五种病毒的包膜 (E) 蛋白二聚体结合的比较结构功能分析。我们证明 C10 Fab 对 ZIKV 和 DENV1 具有高亲和力，但对 DENV2、DENV3 和 DENV4 没有高亲和力。我们进一步表明，C10 与后一种病毒的相互作用需要 E 蛋白构象景观，限制其仅与每个病毒粒子的三个独立表位之一结合。然而，这种有限的亲和力被颗粒的二十面体组织所抵消，这使得 C10 免疫球蛋白的两个 Fab 臂能够到达两个不同的二聚体。因此，表位的几何分布赋予 C10 非凡的中和广度。我们的结果不仅强调了互补位/表位互补性的重要性，而且还强调了以表位为中心的疫苗设计的拓扑分布的重要性。