The Structural Basis of the Flavivirus Replication Process

About the Programme:

The University of Exeter (UoE) and Nanyang Technological University (NTU), Singapore are offering six fully funded postgraduate studentships to undertake collaborative research projects at the two institutions, leading to PhD degrees (split-site) to be conferred either by the UoE or NTU.

Students pursuing these postgraduate research projects will benefit from the unique opportunity to conduct their research at both institutions. Students will be registered at one or other institution, where they will be based for the majority of their time, but will spend at least 12 and not more than 18 months at the partner institution over the duration of the programme. The frequency and length of stays at each institution will be agreed with successful candidates prior to offers being made.

Project Description:
Many members of the mosquito-borne flavivirus are well-known human pathogens such as dengue virus (DENV), Japanese encephalitis virus, West Nile virus, and yellow fever virus and Zika virus. For these RNA viruses, the RNA replication occurs within a replication complex that assembles on the endoplasmic reticulum (ER) of the host cell and comprises both viral proteins and host cofactors. Several proteins of the replication complex constitute validated drug targets because of their crucial function during viral replication. However, a major impediment in developing drugs targeting the DENV replication complex is that both its structure and composition, the interplay between its molecular constituents as well as the precise molecular mechanisms for viral RNA replication are still elusive. The proposed study aims to reveal the structure of the DENV replication complex to elucidate key protein-protein and protein-RNA interactions within it. This structure will enable the development of novel specific antiviral drugs and better vaccines against the infectious flaviviruses.

Methodology: Protein/RNA/Lipid Biochemistry, virology and structural biology. The project will generate the first structure(s) of the DENV RC by combining X-ray crystallography (Dahai Lab) and cryo electron microscopy (cryoEM; Daum Lab) and elucidate the mechanics of this molecular machine at various stages of virus replication.

In summary, these two projects will shed light on the structure and dynamics of the RC from a major group of human viral pathogens and offer novel opportunities in terms of therapeutic interventions to treat dengue and other flavivirus infections.