Cryo-EM structure of a key enzyme in action gives insights into the replication of a human pathogenic virus

Bunyavirales is an order of segmented negative-strand RNA viruses comprising several life-threatening human pathogens for which there is currently no treatment (La Crosse virus, Hantaan virus, Crimean Congo virus, Lassa virus). The replication and transcription of their genome are essential steps of their viral cycle and are catalyzed by a key viral enzyme : the RNA-dependent RNA polymerase. The MEM group at IBS, in collaboration with Dr. Cusack’s group at EMBL Grenoble, describes here the structure of the complete RNA-polymerase of the La Crosse virus obtained at 3 Å resolution by cryo electron microscopy, using data collected on the Glacios cryo-microscopes from IBS and Krios from ESRF. This structure reveals the position and organization of the C-terminal part of the RNA polymerase which includes a cap-binding domain necessary for transcription initiation. Two states could be visualized, pre-initiation and elongation. In particular, this allows to highlight the conformational changes necessary for the formation of a double-stranded 10-base pair RNA in the active site cavity during elongation. The structural details and dynamics of the functional elements identified provide mechanistic insight into bunyavirus transcription and may be crucial for the future development of RNA polymerase inhibitors.

Pre-initiation and elongation structures of full-length La Crosse virus polymerase reveal functionally important conformational change. Benoît Arragain, Grégory Effantin, Piotr Gerlach , Juan Reguera , Guy Schoehn, Stephen Cusack, Hélène Malet. Nature Communications 2020 ;11(1):3590. doi : 10.1038/s41467-020-17349-4.

Contact : Hélène Malet