5LTS

Crystal structure of Lymphocytic choriomeningitis mammarenavirus endonuclease Mutant D118A

Summary for 5LTS

• Entry DOI: 10.2210/pdb5lts/pdb
• Related: 5LTF 5LTN 5T2T
• Descriptor: RNA-directed RNA polymerase L, CHLORIDE ION, SODIUM ION, ... (5 entities in total)
• Functional Keywords: endonuclease, lcmv arenavirus, transferase
• Biological source: Lymphocytic choriomeningitis mammarenavirus
• Cellular location: Virion : A0A059U382
• Total number of polymer chains: 2
• Total formula weight: 47506.86

Authors

Saez-Ayala, M.,Yekwa, E.L.,Canard, B.,Alvarez, K.,Ferron, F. (deposition date: 2016-09-07, release date: 2017-09-13, Last modification date: 2024-01-17)

Primary citation

Saez-Ayala, M.,Yekwa, E.L.,Carcelli, M.,Canard, B.,Alvarez, K.,Ferron, F.
Crystal structures ofLymphocytic choriomeningitis virusendonuclease domain complexed with diketo-acid ligands.
IUCrJ, 5:223-235, 2018

PubMed Abstract: The family, together with the and families, is one of the three negative-stranded RNA viral families that encode an endonuclease in their genome. 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 (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 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.

PubMed: 29765612
DOI: 10.1107/S2052252518001021

Experimental method

X-RAY DIFFRACTION (2.51 Å)