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Exploring the structure and inhibition of a novel epigenetic protein

UCL School of Pharmacy

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Assoc Prof E Woon No more applications being accepted Competition Funded PhD Project (UK Students Only)

About the Project

It is now clear that our environment, diet, and lifestyle can cause our genes to be switched on or off. This is achieved primarily through chemical (or epigenetic) modifications on our DNA, RNA and histone proteins by a complex network of epigenetic proteins. Our lab is particularly fascinated with one class of epigenetic proteins called the AlkB demethylases, which consists of ALKBH1-8 and FTO. They are currently of intense scientific interest because of their strong connections with a range of human diseases, including obesity, type 2 diabetes, and neurodegenerative disorders.

One major focus of our lab is to understand the epigenetic link between the AlkB demethylases and human diseases through the discovery of small molecule inhibitors and smart biosensors to facilitate their cell-based study. To this end, our research has contributed to the first discovery of inhibitors against several AlkB demethylases, notably FTO (Chem. Sci. 2015, 6, 112; Chem. Sci. 2018, 9, 7174), ALKBH5 (Nucleic Acids Res. 2020, 48, e5), ALKBH3 (Chem. Commun. 2016, 52, 6181) and AlkB (J. Med. Chem. 2012, 55, 2173).

Recently, it has been suggested that ALKBH1 is linked to several human cancers, however to date its exact biological function remains unclear. We therefore seek a highly motivated PhD student to work on an ambitious project to solve the first protein-ligand co-crystal structure of ALKBH1. The student will also develop first-in-class ALKBH1 inhibitors to facilitate its mechanistic and functional studies in cells, with a longer-term view to validating its therapeutic potential. This work will advance our understanding of this important protein and may pave the way for novel anticancer therapy.

Main methods and techniques include:
 A range of drug discovery strategies, such as structure-based design, computational modelling approaches, and our in-house Dynamic Combinatorial Mass-Spectrometry (DCMS) technique to design selective inhibitors.
 A range of biochemical and biophysical techniques, such as, CD spectroscopy, MALDI-TOF mass spectrometry, protein thermal shift assay and bioinert HPLC-based assay to evaluate the
 A range of molecular biology techniques (such as gene cloning, protein expression and cell culture) for protein crystallography work and cell-based assays.
 Bioinformatic skills, such as protein sequence analysis and homology modelling.
 Organic and synthetic chemistry skills.

Entry requirements
Applicants are expected to hold a first degree in pharmacy, pharmacology, chemistry, biology or biochemistry (minimum 2.1).
Preferred postgraduate or other work experience: protein expression, protein crystallography, organic synthesis, biochemical assay, and cell culture work. Please see below for additional information.

Person specification
The successful applicants will also need to meet UCL MPhil/PhD entry and English Language requirements. See link for further details

The student stipend will be paid at UCL normal rates (stipend rate for 2020/21 is £17,285 with additional increments in Years 2 and 3 of the studentship).

To be eligible for a full award, applications are invited from UK citizens only. The preferred start date is 8th April 2021.

How to apply
Applications must include CV, personal statement, and the contact details of two referees. Applications should be emailed to Ms Michelle Ward at [Email Address Removed] indicating which studentship is being applied for.

The deadline for applications is Monday 30th November 2020; date for interviews to be confirmed.
The students will join a vibrant, multi-disciplinary research team and will receive extensive training in a broad range of cutting-edge experimental and theoretical skills, with access to exceptional research facilities and expertise at UCL.
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