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The arenavirus multi-domain L protein is involved in viral transcription and replication and represents a promising target for antiviral drugs. The arenavirus matrix protein Z is a small multi-functional protein that inhibits the activities of the L protein. Here we report the structure of Machupo virus L protein in complex with Z determined by cryo-electron microscopy. The Z protein acts as a staple and binds the L protein with 1:1 stoichiometry at the intersection between the PA-C-like region, RNA-dependent RNA polymerase and PB2-N-like region. Binding of the Z protein may lock the multiple domains of L into a fixed arrangement leading to loss of catalytic activity. These results further our understanding of the inhibitory mechanism of arenavirus replication machinery and provide a novel perspective to develop antiviral drugs.<\/jats:p>","DOI":"10.1038\/s41467-021-26432-3","type":"journal-article","created":{"date-parts":[[2021,10,25]],"date-time":"2021-10-25T10:02:56Z","timestamp":1635156176000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Structure of Machupo virus polymerase in complex with matrix protein Z"],"prefix":"10.1038","volume":"12","author":[{"given":"Jun","family":"Ma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuangyue","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0114-0270","authenticated-orcid":false,"given":"Xinzheng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,10,25]]},"reference":[{"key":"26432_CR1","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/S0166-3542(02)00202-4","volume":"57","author":"RN Charrel","year":"2003","unstructured":"Charrel, R. 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