Arenaviruses can cause severe haemorrhagic fever and neurological diseases in humans and other animals, exemplified by Lassa mammarenavirus, Machupo mammarenavirus and lymphocytic choriomeningitis virus, posing great threats to public health^1,2,3,4. These viruses encode a large multi-domain RNA-dependent RNA polymerase for transcription and replication of the viral genome⁵. Viral polymerases are one of the leading antiviral therapeutic targets. However, the structure of arenavirus polymerase is not yet known. Here we report the near-atomic resolution structures of Lassa and Machupo virus polymerases in both apo and promoter-bound forms. These structures display a similar overall architecture to influenza virus and bunyavirus polymerases but possess unique local features, including an arenavirus-specific insertion domain that regulates the polymerase activity. Notably, the ordered active site of arenavirus polymerase is inherently switched on, without the requirement for allosteric activation by 5′-viral RNA, which is a necessity for both influenza virus and bunyavirus polymerases^6,7. Moreover, dimerization could facilitate the polymerase activity. These findings advance our understanding of the mechanism of arenavirus replication and provide an important basis for developing antiviral therapeutics.

沙粒病毒可引起人类和其他动物的严重出血热和神经系统疾病，例如拉沙乳粒病毒、马丘波乳粒病毒和淋巴细胞性脉络丛脑膜炎病毒，对公众健康构成巨大威胁^1,2,3,4。这些病毒编码一种大型的多域 RNA 依赖性 RNA 聚合酶，用于病毒基因组的转录和复制⁵. 病毒聚合酶是主要的抗病毒治疗靶点之一。然而，沙粒病毒聚合酶的结构尚不清楚。在这里，我们报告了 apo 和启动子结合形式的 Lassa 和 Machupo 病毒聚合酶的近原子分辨率结构。这些结构显示出与流感病毒和布尼亚病毒聚合酶相似的整体结构，但具有独特的局部特征，包括调节聚合酶活性的沙粒病毒特异性插入结构域。值得注意的是，沙粒病毒聚合酶的有序活性位点本质上是开启的，不需要 5'-病毒 RNA 的变构激活，这对于流感病毒和布尼亚病毒聚合酶^{6,7都是必需的}. 此外，二聚化可以促进聚合酶活性。这些发现促进了我们对沙粒病毒复制机制的理解，并为开发抗病毒疗法提供了重要基础。