Working in the laboratories of Prof Frank Sobott Dr Anton Calabrese, Astbury Centre at the University of Leeds, GB.
The Astbury Centre at the University of Leeds brings together researchers from across the University – largely from the biological sciences, chemistry and physics – to allow interdisciplinary approaches to be harnessed to understand the molecular basis of life. The Centre has outstanding expertise and research infrastructure in chemical biology, biophysics and all of the major techniques in structural molecular biology. Together, these approaches are combined with analyses of biological function with the ultimate aim of understanding the molecular basis of biological mechanisms in living cells.
Recent investment of more than £17 million in state-of-the-art laboratories for structural biology has put Leeds at the forefront of this research, with electron microscopy, NMR spectroscopy as well as mass spectrometry equipment matching the best in the world.
Viral replication factories in cells
Viral replication factories in cells (sites of viral replication/assembly) are formed by viral non-structural proteins (NSPs) in a number of important human and animal pathogens, including Reoviruses and Rotaviruses (the major cause of >200,000 child deaths per annum). However, the molecular mechanism of viral factory assembly, and their precise role in virus replication remain unexplained. In this project, mass spectrometry (MS) based methods will be developed to understand the structure, dynamics and interactions of the non-structural proteins that mediate viral factory assembly, using non-structural proteins from Rotavirus as a model system. A suite of MS-based tools, including native ion mobility-mass spectrometry, chemical crosslinking, hydrogen-deuterium exchange and fast photochemical oxidation of proteins, will be used to interrogate the structure, conformational dynamics and interactions of the proteins that are essential for viral factory assembly. The ultimate aim of this work is to determine if targeting viral factory formation is a viable, novel strategy to combat viral infections.
You will work under the supervision of Dr Anton Calabrese (co-supervised by Prof Frank Sobott) in Leeds’ world class Biomolecular MS laboratory which houses 7 instruments dedicated to structural mass spectrometry. This is a collaborative project with Dr Alex Borodavka’s laboratory at the University of Cambridge. You will receive training in structural mass spectrometry methodologies, molecular biology techniques and other biophysical approaches to characterise protein-protein and protein-small molecule interactions, and push the limits of current structural MS capabilities.
You are highly motivated, can work independently and have good communication skills. You have a degree in Biochemistry, Chemistry or a related subject. Both UK and EU-based students can apply.
Ribosomes are known to be key cellular machines which translate RNA into protein sequences. While the exact composition of these 2.5 MDa particles is known to vary somewhat between different organisms, allowing the design of antibiotics which specifically interfere with bacterial ribosomes, it has recently also become apparent that heterogeneity in ribosome composition results from differential expression and post-translational modifications (PTM) of ribosomal proteins, altering their function. During viral infection the ribosome composition and structure may be somewhat altered to bias their translational specificity. Ribosomal RNA diversity and the activity of associated factors may generate ‘specialized ribosomes’ that have a substantial impact on how the genomic template is translated into functional proteins.
Mass spectrometry methods are central to analyzing this diversity, starting with post-transcriptional (RNA) and post-translational modifications (proteins). Proteomics is routinely used to map PTM sites, but we aim to paint a much more complete picture of the presence and abundance of all these modifications, including on RNA, and their role for subunit interactions, the overall architecture and stability of the particle as well as subtle conformational changes linked with functional states. This project will provide a unique opportunity to push the boundaries of current MS technology, and contribute significantly to our understanding of the diverse functional roles of specialized ribosomes.
You will work under the supervision of Prof Frank Sobott and Dr Anton Calabrese in collaboration with Prof Ade Whitehouse (Leeds, ribosome biology) in Leeds’ world class Biomolecular MS laboratory which houses 7 instruments dedicated to structural MS. You will receive training in structural mass spectrometry methodologies, molecular biology techniques and other biophysical approaches to characterise protein-protein and protein-RNA interactions, and push the limits of current structural mass spectrometry capabilities.