Service interruption on Monday 11 July from 12:30 to 13:00: all the sites of the CCSD (HAL, EpiSciences, SciencesConf, AureHAL) will be inaccessible (network hardware connection).
Skip to Main content Skip to Navigation
Journal articles

Crystal structures ofLymphocytic choriomeningitis virusendonuclease domain complexed with diketo-acid ligands

Abstract : The Arenaviridae family is one of the three negative stranded RNA viral families encoding an endonuclease in their genome, together with Bunyaviridae and Orthomyxoviridae. The endonuclease domain is carried at the N-terminal 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 stolen from the cellular mRNA by the endonuclease domain in cooperation with other domains of L protein. This molecular mechanism had been demonstrated earlier by our group on the endonuclease of the prototype Lymphocytic ChorioMeningitis virus (LCMV). However, the mode of action of this enzyme is not fully understood as the original structure did not contain the 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 makes it a target of choice for the development of novel antiviral therapy. Here we evaluated using biophysical methods the binding affinity of two diketo acids (DKAs) compounds (DPBA (1) and L-742,001 (2)) onto the LCMV endonuclease domain. We have determined the X-ray structures of LCMV endonuclease domain with catalytic ions in complex with these two compounds, and assessed their efficacy in an in vitro endonuclease activity assay. Based on these data and computational simulation, we synthesized two new DKAs. The LCMV endonuclease exhibits a good affinity for these DKAs making them a good starting point for the design of arenavirus endonuclease inhibitors. Beside being the first example of an arenavirus endonuclease X-ray structure incorporating a ligand, this study is a proof of concept that the design of optimized inhibitors against the arenavirus endonuclease is possible.
Document type :
Journal articles
Complete list of metadata
Contributor : François Ferron Connect in order to contact the contributor
Submitted on : Tuesday, February 16, 2021 - 3:27:08 PM
Last modification on : Wednesday, November 3, 2021 - 5:52:33 AM
Long-term archiving on: : Monday, May 17, 2021 - 6:02:27 PM



Distributed under a Creative Commons Attribution 4.0 International License




Magali Saez-Ayala, Elsie yekwa, Mauro Carcelli, Bruno Canard, Karine Alvarez, et al.. Crystal structures ofLymphocytic choriomeningitis virusendonuclease domain complexed with diketo-acid ligands. International Union of Crystallography journal, International Union of Crystallography 2018, 5 (1), pp.223 - 235. ⟨10.1107/s2052252518001021⟩. ⟨hal-03078366⟩



Record views


Files downloads