The role of non active-site residues in enzyme catalysis

Lead Research Organisation: University of Sheffield
Department Name: Molecular Biology and Biotechnology


The proposed study aims to get to the heart of fundamental questions that are critical to developing our understanding of how enzymes work. Understanding enzyme activity remains a high priority - it is at the core of therapeutic intervention, industrial biotechnology, and synthetic biology. The controlled manipulation of enzyme activity is one of the key elements targeted in each of these areas of research. Enzyme activity has been studied for many decades and many paradigms have evolved but, very recently, tools have been developed that allow the testing of those paradigms with unprecedented levels of detail. We are now able to observe the structure, electronics and dynamics within enzymes at the level of individual atoms. A thorough understanding of these elements and their interplay is crucial to manipulating enzyme activity, and with observation powers at this level of detail, many of traditional paradigms of enzymology are not surviving rigorous testing. To-date, most efforts to develop our understanding of the relationship between protein structure and dynamics, and enzyme activity have focused on active site residues and transition state stabilisation. However, in order for an enzyme to be effective, it has to do much more than preferentially bind the transition state for the reaction. As a minimum, it has to bind and release the substrate(s) and product(s) with appropriate affinities and rates, and it has to set up and release the conformation(s) in which the chemical step occurs. What determines these stabilities and dynamics is largely unknown. Using archetypal phosphoryl transfer enzymes, we will exploit recent advances in structural biology, biophysics and in vivo protein biochemistry to establish how these enzymes control these essential elements of catalysis.


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Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M011151/1 01/10/2015 30/09/2023
1801770 Studentship BB/M011151/1 01/10/2016 30/09/2020 Henry Wood