Abstact

Crimean-Congo haemorrhagic fever virus (CCHFV) is a highly pathogenic member of the Nairoviridae and causes severe disease with high fatality rates. Currently, there are no approved antivirals for CCHFV, but resolving the structure of its RNA-dependent RNA polymerase, termed L protein, could help drug development. Here we report cryogenic electron microscopy structures of the CCHFV L protein in both apo and RNA-bound states at 2.62 A and 2.53 A, respectively. These structures define the molecular architecture of the PA-, PB1- and PB2-like domains within the polymerase core, elucidate the mechanism of promoter recognition and reveal RNA-induced conformational changes that stabilize catalytic elements. Together, these insights provide a structural framework for understanding nairovirus replication and enable structure-based development of polymerase inhibitors.