title: High-resolution structure of the N-terminal endonuclease domain of the Lassa virus L polymerase in complex with magnesium ions.
abstract: Lassa virus (LASV) causes deadly hemorrhagic fever disease for which there are no vaccines and limited treatments. LASV-encoded L polymerase is required for viral RNA replication and transcription. The functional domains of L-a large protein of 2218 amino acid residues-are largely undefined, except for the centrally located RNA-dependent RNA polymerase (RdRP) motif. Recent structural and functional analyses of the N-terminal region of the L protein from lymphocytic choriomeningitis virus (LCMV), which is in the same Arenaviridae family as LASV, have identified an endonuclease domain that presumably cleaves the cap structures of host mRNAs in order to initiate viral transcription. Here we present a high-resolution crystal structure of the N-terminal 173-aa region of the LASV L protein (LASV L173) in complex with magnesium ions at 1.72 Å. The structure is highly homologous to other known viral endonucleases of arena- (LCMV NL1), orthomyxo- (influenza virus PA), and bunyaviruses (La Crosse virus NL1). Although the catalytic residues (D89, E102 and K122) are highly conserved among the known viral endonucleases, LASV L endonuclease structure shows some notable differences. Our data collected from in vitro endonuclease assays and a reporter-based LASV minigenome transcriptional assay in mammalian cells confirm structural prediction of LASV L173 as an active endonuclease. The high-resolution structure of the LASV L endonuclease domain in complex with magnesium ions should aid the development of antivirals against lethal Lassa hemorrhagic fever.
authors: Biomedical Science Research Complex, School of Chemistry, University of St. Andrews, Fife, St. Andrews, United Kingdom.
authors: Gregor D
authors: GD
authors: Wallat
authors: Department of Veterinary and Biomedical Sciences, University of Minnesota, Twin Cities, Saint Paul, Minnesota, United States of America.
authors: Qinfeng
authors: Q
authors: Huang
authors: Laboratory Department of Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
authors: Wenjian
authors: W
authors: Wang
authors: Biomedical Science Research Complex, School of Chemistry, University of St. Andrews, Fife, St. Andrews, United Kingdom.
authors: Haohao
authors: H
authors: Dong
authors: Department of Veterinary and Biomedical Sciences, University of Minnesota, Twin Cities, Saint Paul, Minnesota, United States of America.
authors: Hinh
authors: H
authors: Ly
authors: Department of Veterinary and Biomedical Sciences, University of Minnesota, Twin Cities, Saint Paul, Minnesota, United States of America.
authors: Yuying
authors: Y
authors: Liang
authors: Biomedical Science Research Complex, School of Chemistry, University of St. Andrews, Fife, St. Andrews, United Kingdom ; Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, United Kingdom.
authors: Changjiang
authors: C
authors: Dong
mesh_terms: D004720:Endonucleases / Q000378:metabolism*; D007836:Lassa virus / Q000378:metabolism*; D008274:Magnesium / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D014764:Viral Proteins; D004720:Endonucleases; D008274:Magnesium