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Novel mass spectrometry approaches for protein structural dynamics (funded PhD studentship)


Project Description

High-resolution structural methods such as x-ray crystallography, NMR and now increasingly also EM (where we have excellent equipment in the Astbury Centre at Leeds) are making important contributions to our understanding of biomolecular structure and function.
Determining how proteins interact with other molecules is key in understanding most biological process, development of novel therapeutics and biotechnology. Yet many protein structures are highly dynamic and heterogeneous, making it difficult to capture their complete conformational behavior and assembly pathways using such high-resolution structural snapshots.
Structural proteomics methods which take advantage of recent, cutting-edge mass spectrometry (MS) approaches are coming into their own now as they can map out the conformational space of structurally dynamic, even disordered and unfolded proteins, as well as characterizing heterogeneous assembly pathways, e.g. in amyloid aggregation. While most “traditional” techniques will highlight either the most dominant (stable) form, or an average of all states, structural MS is uniquely powerful in that it can characterize whole ensembles in an unbiased fashion.
This project involves the development and application of cutting-edge structural MS methods, in particular hydrogen-deuterium exchange (HDX) and hydroxyl radical footprinting (fast photo-chemical oxidation of proteins, FPOP), and you will apply them to challenging, high-profile targets such as oligomeric amyloid protein (believed to be the toxic form) as well as membrane proteins. You will also use native MS and ion mobility (see figure), complementary techniques that characterize the stoichiometry and composition of complexes as well as their overall size and shape. In combination with computational approaches (molecular modelling), we can build structural models of complex and dynamic systems.

The PhD candidate will employ advanced experimental and computational methods to determine structure and interactions of key proteins of biopharmaceutical interest, and further develop them using cutting-edge MS equipment available at the Astbury Centre, and our expertise in bioinformatics. The skills gained will be highly valuable for a career in the academic and pharmacological and biotechnological sectors. This position would suit someone with an interest in biomolecular MS method and data analysis development and application.

Academic Contacts
The project supervisors are all part of the Astbury Centre for Structural Molecular Biology at Leeds University, which has some of the best structural biology equipment (e.g. cryo-EM and NMR) and computational resources anywhere. They collaborate on method development in structural proteomics and use of such data for computational modelling of structural dynamics. Professor Sobott’s internationally recognized team has developed and applied structural MS approaches for more than 20 years. His research group develop and modify instrumentation, often in collaboration with instrument manufacturers, but they also apply them widely across the biological sciences. Dr Ault is a senior scientist with 10 year MS experience and manages the MS facility in the Astbury Centre, which houses several Waters Synapt ion mobility platforms including some custom modifications (high-mass operation, ETD, SID, gas-phase HDX) as well as unique high-resolution high-pressure Tofwerk ion mobility and Thermo Orbitrap UHMR instruments, also enabling HDX and FPOP as well chemical cross-linking experiments. Dr Paci is leading the theoretical biophysics group at Astbury Centre, currently focusing on HDX data analysis and structural bioinformatics methods.

Funding Notes

4 year fully-funded School of Molecular and Cellular Biology studentship, starting Oct 2019:
• Research Council Stipend
• UK/EU Tuition Fees
• Research Costs

Candidates should have, or be expecting, minimum 2.1 at undergraduate level in a relevant subject.
English language requirements may also apply.

Please apply online (PhD in Biological Sciences) and include a CV and transcripts: View Website

Related Subjects

How good is research at University of Leeds in Biological Sciences?

FTE Category A staff submitted: 60.90

Research output data provided by the Research Excellence Framework (REF)

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