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Time resolved crystallography of multifunctional heme enzymes


   School of Life Sciences

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  Dr J Worrall, Prof Mike Hough, Dr R Owen  No more applications being accepted  Funded PhD Project (UK Students Only)

About the Project

A joint 4-year PhD studentship between the University of Essex and Diamond Light Source

Project description: Capturing the time resolved structures of enzymes undergoing catalysis is a grand challenge of structural biology. While this approach has been well developed for light activated reactions, the general approach of mixing enzyme crystals with activating reagents and substrates has only been applied to a handful of cases to date. In this project, serial crystallography (combining data from many thousands of small crystals to form a complete dataset) will be used to obtain structures at ambient (i.e. non-cryogenic) temperatures using microcrystals for two different multifunctional enzymes.

Data will be obtained using synchrotron and X-Ray free electron laser sources (XFELs) and X-Ray emission and other spectroscopies will be used to identify reaction intermediate states. Enzyme reactions will be initiated by mixing of crystals with either hydrogen peroxide or molecular oxygen and reactions followed at microseconds to seconds time points. The heme enzymes to be studied are (i) the remarkable multifunctional globin dehaloperoxidase (DHP) that is able to catalyse oxidase, peroxidase, oxygenase and peroxygenase reactivities; (ii) catalase peroxidase (KatG). DHP appears able to tune reactivity based on the substrates encountered although the mechanisms for this remain unclear in the absence of time resolved structures of reactions. KatG activates the pro-drug isonicotinic acid hydrazide (INH) a first line of treatment for tuberculosis for over 60 years. Despite the success of INH, the activation mechanism remains elusive. Neither enzyme has been studied in a time resolved manner.

Outstanding training opportunities are available within this studentship, with the opportunity to work at world leading X-Ray sources and engage with a broad collaborative team based at the University of Essex (https://www.essex.ac.uk) and Diamond Light Source . (https://www.diamond.ac.uk/Home.html) primarily at beamlines I24 and VMXi.

Studentship details: The studentship is fully funded for 4 years and will commence on 6th October 2022. The student will be expected to spend 50% of their time at the University of Essex and 50% at Diamond Light Source throughout the project period. A stipend of £17,920 is provided in the first year, which will increase each year to a final value of £18,896 and full UK tutition fees covered. Funds for travel and conference attendance will also be available. To be eligible for this award you must be a Home student (i.e. UK national meeting residency requirements) and have or be expected to obtain a first or upper second class BSc (or equivalent) in biochemistry, chemistry or biophysics or a Masters in a related area.

Further Information: Please contact Dr Jonathan Worrall ([Email Address Removed]), Prof Mike Hough ([Email Address Removed]) or Dr Robin Owen ([Email Address Removed]) for further information about the project. Please also see Diamond Light Source via https://www.diamond.ac.uk/Careers/Students/Studentships/2022-projects/2022-STU0436.html

How to apply for this studentship: To apply, email your CV and a 500 word statement outlining your motivation for applying to this studentship to Emma Revill ([Email Address Removed]). There is no deadline for applications, applications will be assessed as they are received.

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