Molecular basis of influenza ribonucleoprotein complex assembly and processive RNA synthesis
Ruchao Peng, Xin Xu, Binod Nepal, Yikang Gong, Fenglin Li, Max Ferretti, Mingyang Zhou, Kristen W. Lynch, George M. Burslem, Sandhya Kortagere, Ronen Marmorstein, Yi‐Wei Chang
Abstract
Influenza viruses replicate and transcribe their genome in the context of a conserved ribonucleoprotein (RNP) complex. By integrating cryo-electron microscopy single-particle analysis and cryo-electron tomography, we define the influenza RNP as a right-handed, antiparallel double helix with the viral RNA encapsidated in the minor groove. Individual nucleoprotein subunits are connected by a flexible tail loop that inserts into a conserved pocket in its neighbor. We visualize the viral polymerase in RNP at different functional states, revealing how it accesses the RNA template while maintaining the double-helical architecture of RNP by strand sliding. Targeting the tail loop binding interface, we identify lead compounds as potential anti-influenza inhibitors. These findings elucidate the molecular determinants underpinning influenza virus replication and highlight a promising target for antiviral development.