Research Associate / Senior Research Associate in Structure-Guided Drug Design

The role

We have discovered that proteins of our innate immune system called C-reactive protein (CRP) can form distinct oligomeric patterns, and the shape of these patterns dictates how our immune system responds to threats. This can be either a robust inflammatory response (good for clearing infections), or a more gently silent clearance (good for removing cellular debris and limiting auto-immunity). When these responses are dysregulated, we are less able to fight infections and more likely to develop autoimmune diseases.

We have recently solved structures revealing that CRP can form different shapes, and it is these shapes that dictate the immunological function. This is therefore a reversible switch, whereby two structures have different immunological outcomes: inflammation by 2D arrays activating complement, vs silent clearance by decamers causing agglutination. Control of this switch will give us control of the immune system, which can be used to treat a variety of diseases, including autoimmune or infectious diseases.

You will be part of a team using synthetic and structural biology to understand and control the human immune system. Here, the PDRA will utilise cryoEM, AI-based structure predictions, rational protein engineering and other techniques to demonstrate the potential of structure-guided drug design to control CRP activity. This project will lead to a greater understanding of pentraxin biology and immune system activation, and will produce drug candidates to control CRP activation. Furthermore, this project will exemplify the possibility of targeting other members of the pentraxin family, which are associated with numerous infections and neurodegenerative diseases.

What will you be doing?

• Solve the structures of CRP in complex with existing and new protein and peptide binders that are able to modulate the activity of CRP.
• Perform structure-guided drug design and development to gain control over CRP effector functions, including agonists and antagonists.
• Lead the development of binders able to modulate the structure/function of CRP. These include synthesising/expressing cyclic peptides, small molecules, nanobodies, and de-novo designed proteins.
• Perform a suite of biophysical assays to explore the impact of binders on CRP function.
• Perform cryoEM to solve structures of CRP in complex with binders, and use these data to perform structure-guided drug design.

You should apply if

• Working experience with molecular biology techniques, protein expression and protein purification techniques.
• High-level knowledge of protein structure.
• Working experience with biochemical and biophysical assays.
• Knowledge of cryoEM and software for protein structure determination.
• Keen interest in synthetic biology and bioengineering
• Proven ability to act as an independent researcher and proactively drive the development and direction of a research project.

Additional information

For informal queries about the role please contact: Thomas Sharp, t.sharp@bristol.ac.uk

This advert will close at 23:59 UK time on Monday 12th August 2024

Interviews are anticipated to be held on either Wednesday 28th of August or Friday 30th of August 2024.

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