Postdoctoral Fellow: Fast elucidation of RAS protein-ligand structures and dynamics by NMR2,
Postdoctoral Fellow: Fast elucidation of RAS protein-ligand structures and dynamics by NMR2,
AstraZeneca, The Discovery Centre, Cambridge Biomedical Campus, Cambridge, UK
Competitive salary and benefits
Introduction to the role
Do you have a passion for NMR, biophysics, and computational methods? Would you like to apply your expertise to tackle the key RAS oncoprotein by finding and characterising protein-fragment structures to discover novel inhibitors? Then join the BioNMR group within the Discovery Sciences, UK Biophysics team at AstraZeneca to push the boundaries of science!
Discovery Sciences is a global function supporting all of AstraZeneca’s R&D therapy organisations, delivering to drug projects for Oncology and Biopharmaceuticals as well as collaborating with our Alexion colleagues on rare disease projects. The UK Biophysics team within Discovery Sciences applies industry-leading expertise and state-of-the-art instrumentation to support the identification and characterisation of validated hits, leads, and drug candidates. The AZ Biophysics team includes a world-class BioNMR department, with state of the art instrumentation and we are looking for a passionate NMR spectroscopist to join our team as a postdoctoral fellow.
In this exciting project in collaboration with Prof. Julien Orts from the University of Vienna, you will use solution NMR in combination with cutting-edge computational methods to discover and structurally characterise novel inhibitors against various RAS mutants. NMR2 is a solution NMR molecular replacement method, allowing the determination of protein-ligand complex structures with minimal assignment information (JMedChem 65, 5565-5574 ; JACS 138, 4393-4400 ). This project aims to apply NMR2 in the context of fragment binding to RAS to provide new insights into the structure and dynamics of protein-ligand complexes and to find structural and dynamical patterns to better understand and guide selectivity across different RAS mutants. These inhibitors will pave the way for the development of new therapeutics for currently intractable tumours.
Based in our new Discovery Centre you will work in our state-of-the-art global R&D centre in the heart of the Biomedical Campus in Cambridge, one of the most exciting bioscience hotspots in the world.
This is a 3-year programme, with an initial 2-year period and a 1-year merit-based extension.
Key Accountabilities
Produce labelled and unlabelled proteins, following well-established in-house protocols.
Carry out NMR-based fragment screens against selected RAS mutants.
Extend the existing NMR2 method to generate protein-ligand structures from mixtures of fragments and apply this to validated hits from the fragment screens.
Further extend the NMR2 approach using AlphaFold models for molecular replacement and compare the results with experimental X-ray starting structures.
Use NMR relaxation data to augment and refine the NMR conformational ensemble to gain an understanding of the dynamic protein landscape.
Finally, incorporate data from different mutants into a machine learning (ML) model to predict features and properties of untested compounds.
Essential Skills/Experience
Excellent analytical and problem-solving skills.
PhD (or equivalent) with background in NMR spectroscopy, physical chemistry or (bio)-physics.
Basic expertise of scripting in R, Python or other programming languages.
Good communication skills.
Highly motivated and ability to work in a team.
Desirable Skills/Experience
Experience in biochemistry and expression and purification of labelled protein.
Knowledge of other orthogonal biophysical techniques, such as SPR, ITC or DSF.
Knowledge of drug discovery or medicinal chemistry.
At AstraZeneca, we thrive in an environment where the brightest minds come together in an inclusive culture. We are committed to making a difference by fusing data and technology with scientific innovations to achieve breakthroughs. Our collaborative approach with academia, biotech, and industry partners allows us to create significant impacts on disease treatment. Join us to explore new scientific horizons and contribute to life-changing medicines.
Ready to make a difference? Apply now!
AZ’s Postdoc Programme: https://careers.astrazeneca.com/postdocs-astrazeneca
Life at AstraZeneca: https://careers.astrazeneca.com/life-at-astrazeneca
This is what we’re made of: https://www.youtube.com/watch?v=pmFx_jr2eFo&t=2s
AstraZeneca embraces diversity and equality of opportunity. We are committed to building an inclusive and diverse team representing all backgrounds, with as wide a range of perspectives as possible, and harnessing industry-leading skills. We believe that the more inclusive we are, the better our work will be. We welcome and consider applications to join our team from all qualified candidates, regardless of their characteristics. We comply with all applicable laws and regulations on non-discrimination in employment (and recruitment), as well as work authorisation and employment eligibility verification requirements.
