The structure and functional studies of Ebola and rabies virus L-polymerase

Rabies and Ebola are highly dangerous zoonotic viruses, which invariably cause death in human individuals who are not able to receive immediate medical treatment, upon infection.  Rabies virus is a major human pathogen and the World Health Organisation estimates that it causes at least 55000 deaths worldwide, the vast majority in the Asia and Africa.  Rabies is one of the oldest established human diseases; in contrast Ebola is a recently emergent virus that was first discovered in 1976. Ebola virus, like Rabies, is highly pathogenic and recent outbreaks in West Africa are currently of major concern and have been widely reported in the Media.

At present there are no effective drug treatments for viruses such as Rabies and Ebola.  The project aims ultimately to make it possible to find antivirals targeted to an enzyme - the RNA polymerase - central to the life cycle of these viruses. 

Our understanding of the structure and mechanism of action of the RNA-dependent RNA polymerase (RdRP) of members of the monanegavirales, such as Rabies and Ebola viruses is rudimentary.  The L-polymerase is a large (250kDa) molecule that house all the apparatus to synthesise full capped viral mRNA.  We have recently determined the structure of a C-terminal fragment of Human metapneumovirus (HMPV) L polymerase, which has methyltransferase activity and is involved in viral CAP synthesis. HMPV is a close relative of Ebola. One aim of this project is to structurally characterise the homologous region of Ebola and rabies Virus L, with the aim of solving the structures of complexes of this fragment with co-factors and ligands by X-ray crystallography.  We have also solubly expressed the full length L-polymerase of Rabies virus and the second aim would be to structurally characterise the full length L-pol by X-ray crystallography or cryo-EM at close to atomic resolution, using the in-house K2 electron detector.  We have collaborations with groups in The Pasteur Institute and CNRS & Aix Marseille Université to understand the structural results in terms of the function of the polymerase in the context of the viral lifecycle.

Contact Supervisor

Professor Jonathan M Grimes

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