Structural and Mechanistic Biology at the RNA/Ligand Interface

The Network will investigate aspects of the biological consequences of RNAprotein/ligand interactions using multidisciplinary approaches.

One of the projects addresses an essential feature of the assembly, and by implication the disassembly/uncoating, of positive sense single-stranded RNA viruses, the largest group of viral pathogens.

Recent discoveries by the Leeds-York team have revealed an unsuspected, and likely evolutionarily
conserved, assembly mechanism based on multiple degenerate contacts between viral coat proteins and
segments of their cognate genomes termed Packaging Signals. Interrupting such contacts with small
molecular weight ligands causes error-prone and incomplete assembly.

We are currently establishing that similar mechanisms occur in plant, animal and human viruses and have obtained preliminary evidence that they do.

The student will join the group to extend the characterisation of PS-CP interactions for these and other pathogens, including Foot and Mouth Disease Virus and plant pathogens such as Turnip Crinkle Virus.

The second project, lead by York, will involve fundamental investigations of RNA recognition by proteins
involved in the RNA silencing response. The principal tool in these studies will be high field NMR investigations of structure and dynamics of these molecules in solution. RNA silencing has as yet largely untapped potential for therapeutic intervention.

This project will determine fundamental mechanisms at the core of this process and illuminate the mode-of-action of a family of small molecules that regulate it.

The third project deals with an alternative splicing factor and its role(s) in protein homeostasis that in turn is
linked to a number of disease states including neurodegenerative conditions, cancer and diabetes.

Again NMR will be the major investigative tool but coupled with small ligand screening for compounds that modulate the primary RNA processing activity of the protein.

These projects fit a number of BBSRC Priority Areas: Crop Science, & Animal Health (Project 1) and
Technology Development (Projects 1-3).

Awarded as part of the White Rose BBSRC DTP

Network Lead – Peter G Stockley

Studentship topic: Defining a novel assembly pathway in ssRNA viruses.

Principal Supervisor – Peter G Stockley – Leeds

Co=Supervisor – Reidun Twarock – York

Studentship topic: Evaluating the role of protein dynamics in double-stranded RNA recognition

Principal Supervisor – Michael Plevin – York

Co-Supervisor – Mike Williamson – Sheffield

Studentship topic: NMR screening of small molecule inhibitors targeting endonuclease activity of an ER
stress sensor Ire1

Principal Supervisor – Beining Chen – Sheffield

Co-Supervisor – Anastasia Zhuravleva – Leeds