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The endonuclease domain is at the N-terminus of the L protein, a multifunctional protein that includes the RNA-dependent RNA polymerase. The synthesis of mRNA in arenaviruses is a process that is primed by capped nucleotides that are `stolen' from the cellular mRNA by the endonuclease domain in cooperation with other domains of the L protein. This molecular mechanism has been demonstrated previously for the endonuclease of the prototype<jats:italic>Lymphocytic choriomeningitis virus<\/jats:italic>(LCMV). However, the mode of action of this enzyme is not fully understood as the original structure did not contain catalytic metal ions. The pivotal role played by the cap-snatching process in the life cycle of the virus and the highly conserved nature of the endonuclease domain make it a target of choice for the development of novel antiviral therapies. Here, the binding affinities of two diketo-acid (DKA) compounds (DPBA and L-742,001) for the endonuclease domain of LCMV were evaluated using biophysical methods. X-ray structures of the LCMV endonuclease domain with catalytic ions in complex with these two compounds were determined, and their efficacies were assessed in an<jats:italic>in vitro<\/jats:italic>endonuclease-activity assay. Based on these data and computational simulation, two new DKAs were synthesized. The LCMV endonuclease domain exhibits a good affinity for these DKAs, making them a good starting point for the design of arenavirus endonuclease inhibitors. In addition to providing the first example of an X-ray structure of an arenavirus endonuclease incorporating a ligand, this study provides a proof of concept that the design of optimized inhibitors against the arenavirus endonuclease is possible.<\/jats:p>","DOI":"10.1107\/s2052252518001021","type":"journal-article","created":{"date-parts":[[2018,2,22]],"date-time":"2018-02-22T14:08:40Z","timestamp":1519308520000},"page":"223-235","update-policy":"https:\/\/doi.org\/10.1107\/cm_01","source":"Crossref","is-referenced-by-count":20,"title":["Crystal structures of<i>Lymphocytic choriomeningitis virus<\/i>endonuclease domain complexed with diketo-acid ligands"],"prefix":"10.1107","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8726-0053","authenticated-orcid":true,"given":"Magali","family":"Saez-Ayala","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9038-0366","authenticated-orcid":true,"given":"Elsie Laban","family":"Yekwa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5888-4556","authenticated-orcid":true,"given":"Mauro","family":"Carcelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Canard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6108-6966","authenticated-orcid":true,"given":"Karine","family":"Alvarez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8351-4992","authenticated-orcid":true,"given":"Fran\u00e7ois","family":"Ferron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"329","published-online":{"date-parts":[[2018,2,22]]},"reference":[{"key":"lz5019_bb1","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1107\/S0907444912001308","volume":"68","author":"Afonine","year":"2012","journal-title":"Acta Cryst. 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