Cap binding and immune evasion revealed by Lassa nucleoprotein structure

Lassa fever virus (LASV) causes thousands of deaths yearly and is a biological threat agent, for which there is no vaccine and limited therapy1. The nucleoprotein (NP) of LASV plays essential roles in viral RNA synthesis and immune suppression2-6, the molecular mechanisms of which are poorly understood. Here, we report the crystal structure of LASV NP at 1.80 Angstrom resolution, which reveals N- and C-domains with structures unlike any of the reported viral NPs7-10. The N domain folds into a novel structure with a deep cavity for binding the m7GpppN cap structure that is required for viral RNA transcription, whereas the C domain contains 3′-5 ′ exoribonuclease activity involved in suppressing interferon induction. This is the first X-ray crystal structure solved for an arenaviral NP, which reveals its unexpected functions and suggests unique mechanisms in cap binding and immune evasion. These findings provide great potential for vaccine and drug development. Several arenaviruses including LASV can cause severe viral haemorrhagic fevers in humans with high morbidity and mortality, to which there is no vaccine and limited treatments 1,11-13. These pathogenic arenaviruses are public health threats and potential biological threat agents. LASV, like other arenaviruses, is a single-stranded ambisense RNA virus wit