Harmer Group

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Enzyme cascades and their applications

Enzymes are nature’s catalysts. They are molecules that make reactions in biology work faster. All the chemical changes needed in living systems rely on enzymes speeding up reactions at the right time. Our work seeks to understand sets of enzymes working together – a “cascade” – to drive desirable reactions. We engineer some enzymes using evolutionary methods. We then apply this understanding to practical problems. Our key examples are: the production of sugars for use in vaccines against bacteria; and chemical transformations for drug manufacture. Our work will help to deliver vaccines or drugs at scale using fewer resources and producing less waste. It will help both with overcoming antimicrobial resistance, and achieving a green future.

Time-resolved structural studies of enzymes

The key steps in enzyme catalysis occur quickly in rare events on a molecular timescale. To gain deeper understanding of how enzymes work, we want to determine the structure of enzymes as they move through the catalytic cycle. Achieving this requires the latest structural biology innovations. We aim to use our well-characterised systems from the enzyme cascade projects to work with synchrotron experts to catch enzymes in the act of catalysis and better understand how enzymes achieve their amazing speeding up of reactions.

Research Team

Anil Jamithireddy (Postdoc)

Courtney Tremlett (PhD)

William Stuart (PhD)

Freddie Moore (PhD)

Opportunities

Funded PhD opportunities

Living Systems Institute PhD programme for 2024 entry:

Designed fluorescent paired-protein small molecule detectors for Living Systems

Supervisors: Nicholas Harmer and JJ Phillips

This project offers the existing opportunity to learn the latest methods in protein design, a field that is rapidly developing and promises to revolutionise molecular science in the next few years. In this project, you will learn how to design proteins and apply this to developing highly specific sensor proteins for target small molecules and peptides. You will learn how to prepare and test the designed sensors using a suite of advanced methods (including hydrogen-deuterium exchange mass spectrometry, X-ray crystallography, and cryo-electron microscopy). You will work with expert colleagues and collaborators to identify high value molecules to design sensor against that will open new experiments in their fields. This project will offer the opportunity to make an impact across multiple different areas of biological and chemical science.

This project will particularly appeal to students with broad interests who are happy to use both computational and laboratory-based methods in their research, and who value the opportunity to work with other groups to influence diverse research areas. Some experience in looking at protein structures would be a strong advantage in developing the design aspects of the project. LSI has a strong structural biology grouping using the latest techniques to gain a molecular understanding of life. You will join an integrated PhD community who organise their own programme of scientific and social events. LSI provides an ideal environment for a successful PhD in this area.

Click here to apply

Developing a novel drug therapy for Neurofibromatosis type 1 tumours

Supervisors: Professor Benjamin Housden and Professor Nic Harmer

The aim of this project is to develop new and effective drug treatments for the tumours associated with neurofibromatosis type 1 (NF1). This is important because current drug therapies are not effective in all patients and can cause serious side effects. NF1 tumours form when the NF1 gene is mutated in a single cell within the patient’s body. This mutation stimulates the cell to grow and divide, resulting in a tumour.

In our previous work, we used genome wide genetic screens to find candidate drug-targets to treat NF1 tumours. This resulted in 46 high-confidence candidates. In this project, the student will first use in silico analysis of the candidate targets to identify those that are most susceptible to drug inhibition.  Next, we will investigate the potential of the top-ranked candidates using cell culture models of NF1 tumours. Finally, the student will test novel inhibitors to identify the most promising route to an effective therapy for this disease.

Click here to apply

SWBio DTP (CASE project: offers an enhanced stipend from the CASE partner)

Time-resolved kinetic and structural understanding of essential enzymes to develop novel herbicides

Supervisors: Professor Nic Harmer, Professor Jim Spencer (University of Bristol), Dr. Christian Noble (Syngenta)

This project offers the existing opportunity to use the latest structural biology methods to impact the
development of new herbicides to help crop security. In this project, you will determine a structural movie of the
enzymatic action of two herbicide targets. These exciting results will highlight the optimal strategies for designing
new herbicides and provide a new level of detailed understanding of the enzymes. The project will offer the
opportunity to learn techniques at the cutting edge of structural biology and to make a significant impact on food
production. As a student on the project, you will learn a strong range of techniques. Key methods will be protein
production and purification, crystallisation and structure determination, and enzyme studies to complement the
structural results. The supervisors are experts in all stages of this work and have strong experience of developing
similar projects. This project will have expert supervisors in Exeter and Bristol, offering the opportunity to
experience two different research environments, access a wider range of expertise, and interact with other DTP
students more extensively.

This project will be undertaken in collaboration with Syngenta, and as part of the project you will take a three
month placement at Syngenta’s site at Jealott’s Hill. This placement will be timed to obtain maximum benefit from
the opportunity and will most likely be taken once results are established for one enzyme and can be followed up
effectively with Syngenta. Syngenta will provide an additional supervisor to give insight into the herbicide
development process and further support your development.

Click here to apply: deadline Monday 4th December