Integrative Structural Biology in Viral RNA Synthesis Machinery

Measles virus (MeV) is a highly contagious pathogen that causes significant morbidity worldwide. Despite the availability of an effective vaccine, MeV continues to cause outbreaks, highlighting the need for alternative treatments that target viral replication and pathogenesis. The MeV polymerase complex, consisting of the large protein L and phosphoprotein P, plays a critical role in RNA transcription and replication, making it a promising target for antiviral strategies. However, key aspects of the complex’s structure and function remain poorly understood, including how it interacts with RNA, how it distinguishes between transcription and replication, how the L and P proteins work together during RNA synthesis, and how the polymerase complex cooperates with the nucleoprotein N during RNA replication. Additionally, the role of other factors in regulating polymerase activity has yet to be well defined. Our overall objectives for the proposed funding period are to (1) determine the structural and functional properties of MeV polymerase in its various functional states, including initiation, elongation, and termination; (2) explore the dynamics of the polymerase-nucleocapsid interaction; and (3) investigate the role of the viral co-factor C protein in regulating RNA synthesis. We hypothesize that understanding these interactions will reveal insights into the mechanisms of how MeV polymerase functions and how its regulation can be targeted for therapeutic intervention. To address these questions, we will utilize a combination of cryo-electron microscopy (cryo-EM), protein-RNA biochemistry, and viral minigenome systems. The proposed work aims to provide new insights into the structural and functional mechanisms governing MeV replication, with the potential to identify new targets for antiviral therapies that could help control MeV outbreaks. Project Number: 1R35GM162600-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: BIN LIU | Institution: UNIVERSITY OF MINNESOTA, MINNEAPOLIS, MN | Award Amount: $437,250 | Activity Code: R35 | Study Section: Special Emphasis Panel[ZRG1 MBBC-J (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11259282