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Prof A Berry
Prof Neil Ranson
Prof Michael Webb
No more applications being accepted
Competition Funded PhD Project (European/UK Students Only)
About the Project
Polyketide and non-ribosomal peptide ‘megasynthases’ are responsible for the production of many important antibiotics. This project will use cryo-electron microscopy to determine new 3D structures of these exciting and important biosynthetic machines at the highest possible resolution. It will provide a thorough training in modern structural biology, in one of the best-equipped cryo-EM facilities in the world. The genes for some of the protein modules that form the megasynthase have already been cloned and expressed in E. coli, and this project will build on that experience to clone the remainder. This will allow us to characterize and engineer individual proteins as well as to understand their organization into a natural multimeric machine and provide a way to understanding the overall architecture of these important enzymes ready for a ‘molecular lego’ approach to the bioengineering new antibiotics.
Funding Notes
BBSRC White Rose Mechanistic Biology DTP 4 year studentship.
Studentships covers UK/EU fees and stipend (c.£14,553) for 4 years to start in Oct 2018. Applicants should have/be expecting at least a 2.1 Hons. degree in a relevant subject. EU candidates require 3 years of UK residency in order to receive full studentship.
Not all projects advertised will be funded; the DTP will appoint a limited number of candidates via a competitive process and the projects selected by the successful candidates will be funded.
There are 2 stages to the application process. Please see our website for more information: http://www.fbs.leeds.ac.uk/postgraduate/phdopportunities.php
Studentships covers UK/EU fees and stipend (c.£14,553) for 4 years to start in Oct 2018. Applicants should have/be expecting at least a 2.1 Hons. degree in a relevant subject. EU candidates require 3 years of UK residency in order to receive full studentship.
Not all projects advertised will be funded; the DTP will appoint a limited number of candidates via a competitive process and the projects selected by the successful candidates will be funded.
There are 2 stages to the application process. Please see our website for more information: http://www.fbs.leeds.ac.uk/postgraduate/phdopportunities.php
References
BERRY:
Timms, N., Windle, C.L., Polyakova, A., Ault, J.R., Trinh, C.H., Pearson, A., Nelson, A. and Berry, A.(2013) Structural Insights into the recovery of aldolase activity in N-acetylneuraminic acid lyase by replacement of the catalytically active lysine with -thialysine by using a chemical mutagenesis strategy. Chembiochem, 14, 474-481
Pearsall, S.M., Rowley, C.N. and Berry, A. (2015) Advances in pathway engineering for natural product biosynthesis. Chemcatchem dx.doi.org/10.1002/cctc.201500602
Windle, C.L., Simmons, K., Ault, J.R., Trinh, C.H., Nelson, A., Pearson, A.R. and Berry, A. (2017) Extending enzyme molecular recognition with an expanded amino acid alphabet. Proc Natl Acad Sci USA, 114, 2610-2615. DOI:10.1073/pnas.1616816114
Cross, L.L., Paudyal, R., Kamisugi, Y., Berry, A., Cuming, A.C., Baker, A. and Warriner, S.L. (2017) Towards designer organelles by subverting the peroxisomal import pathway. Nature Comms. 8, Article number: 454. Doi: 10.1038/s41467-017-00487-7
RANSON:
Patel, N., White, S.J., Thompson, R.F., Weiß, E.U., Bingham, R., Zlotnick, A., Dykeman, E., Twarock, R., Ranson, N.A. & Stockley, P.G. (2017). The HBV RNA pregenome encodes specific interactions with the viral core protein that can promote nucleocapsid assembly. Nature Microbiology, DOI:10.1038/nmicrobiol.2017.98
Iadanza, M.G., Higgins, A.J., Schiffrin, R., Calabrese, A., Brockwell, D.J., Ashcroft, A.E. Radford, S.E. & Ranson, N.A. (2016). Lateral opening of the intact β-barrel assembly machinery captured by cryo-EM Nature Comms. DOI:10.1038/ncomms12865.
Hesketh, E.L., Meshcheriakova, Y., Dent, K.C., Saxena, P., Thompson, R.F., Cockburn, J.J.B, Lomonossoff, G.P. & Ranson, N.A. (2015). Mechanisms of assembly and genome packaging in an RNA virus revealed by high-resolution cryo-EM. Nature Comms., DOI:10.1038/ncomms10113
Goodchild, S.C., Sheynis, T., Thompson, R., Tipping, K.W., Xue, W.F., Ranson, N.A., Beales, P.A., Hewitt, E.W. & Radford, S.E. (2014). β2-Microglobulin Amyloid Fibril-Induced Membrane Disruption Is Enhanced by Endosomal Lipids and Acidic pH. PLoS One, 9 (8), e104492
WEBB:
Arnott, Z.L.P., Nozaki, S., Monteiro, D.C.F., Morgan, H.E., Pearson, A.R., Niki, H. and Webb, M.E. (2017) Mechanism of regulation of pantothenate biosynthesis by the PanD-PanZ.AcCoA complex reveals an additional mode of action for the antimetabolite N-pentyl pantothenamide (N5-Pan) Biochemistry (2017) doi: 10.1021/acs.biochem.7b00509
Morrison, P.M., Balmforth, M.R., Ness, S.W., Williamson, D.J., Rugen, M.D., Turnbull, W.B. & Webb, M.E. Confirmation of a protein-protein interaction in the pantothenate biosynthetic pathway using Sortase-mediated labelling ChemBioChem (2016) 17 753-758
Timms, N., Windle, C.L., Polyakova, A., Ault, J.R., Trinh, C.H., Pearson, A., Nelson, A. and Berry, A.(2013) Structural Insights into the recovery of aldolase activity in N-acetylneuraminic acid lyase by replacement of the catalytically active lysine with -thialysine by using a chemical mutagenesis strategy. Chembiochem, 14, 474-481
Pearsall, S.M., Rowley, C.N. and Berry, A. (2015) Advances in pathway engineering for natural product biosynthesis. Chemcatchem dx.doi.org/10.1002/cctc.201500602
Windle, C.L., Simmons, K., Ault, J.R., Trinh, C.H., Nelson, A., Pearson, A.R. and Berry, A. (2017) Extending enzyme molecular recognition with an expanded amino acid alphabet. Proc Natl Acad Sci USA, 114, 2610-2615. DOI:10.1073/pnas.1616816114
Cross, L.L., Paudyal, R., Kamisugi, Y., Berry, A., Cuming, A.C., Baker, A. and Warriner, S.L. (2017) Towards designer organelles by subverting the peroxisomal import pathway. Nature Comms. 8, Article number: 454. Doi: 10.1038/s41467-017-00487-7
RANSON:
Patel, N., White, S.J., Thompson, R.F., Weiß, E.U., Bingham, R., Zlotnick, A., Dykeman, E., Twarock, R., Ranson, N.A. & Stockley, P.G. (2017). The HBV RNA pregenome encodes specific interactions with the viral core protein that can promote nucleocapsid assembly. Nature Microbiology, DOI:10.1038/nmicrobiol.2017.98
Iadanza, M.G., Higgins, A.J., Schiffrin, R., Calabrese, A., Brockwell, D.J., Ashcroft, A.E. Radford, S.E. & Ranson, N.A. (2016). Lateral opening of the intact β-barrel assembly machinery captured by cryo-EM Nature Comms. DOI:10.1038/ncomms12865.
Hesketh, E.L., Meshcheriakova, Y., Dent, K.C., Saxena, P., Thompson, R.F., Cockburn, J.J.B, Lomonossoff, G.P. & Ranson, N.A. (2015). Mechanisms of assembly and genome packaging in an RNA virus revealed by high-resolution cryo-EM. Nature Comms., DOI:10.1038/ncomms10113
Goodchild, S.C., Sheynis, T., Thompson, R., Tipping, K.W., Xue, W.F., Ranson, N.A., Beales, P.A., Hewitt, E.W. & Radford, S.E. (2014). β2-Microglobulin Amyloid Fibril-Induced Membrane Disruption Is Enhanced by Endosomal Lipids and Acidic pH. PLoS One, 9 (8), e104492
WEBB:
Arnott, Z.L.P., Nozaki, S., Monteiro, D.C.F., Morgan, H.E., Pearson, A.R., Niki, H. and Webb, M.E. (2017) Mechanism of regulation of pantothenate biosynthesis by the PanD-PanZ.AcCoA complex reveals an additional mode of action for the antimetabolite N-pentyl pantothenamide (N5-Pan) Biochemistry (2017) doi: 10.1021/acs.biochem.7b00509
Morrison, P.M., Balmforth, M.R., Ness, S.W., Williamson, D.J., Rugen, M.D., Turnbull, W.B. & Webb, M.E. Confirmation of a protein-protein interaction in the pantothenate biosynthetic pathway using Sortase-mediated labelling ChemBioChem (2016) 17 753-758
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Career overview
Professor Alan Berry is a Professor of Molecular Enzymology at the University of Leeds, where he is part of the School of Molecular and Cellular Biology. He obtained a BSc and PhD in 1983 from the University of Southampton. His postdoctoral work was conducted at ETH-Zurich and the University of Cambridge. He was appointed as a lecturer in 1994 and became a Senior Lecturer in 1997. Professor Berry''s research focuses on protein engineering, particularly the study of the relationship between enzyme structure and function, with significant applications in the design of new enzymes. His laboratory employs both rational redesign and directed evolutionary approaches to modify the specificity and chemistry of selected enzymes, including fructose bisphosphate aldolases and other enzymes involved in the biosynthesis of sialic acid. His research is supported by the BBSRC and The Wellcome Trust. Professor Berry has held various academic roles, including Director of Postgraduate Research Studies and Chair of the Graduate School Committee.
Research interests
Professor Berry''s research focuses on protein engineering, specifically the study of the relationship between structure and function of enzymes. His laboratory employs both rational redesign and directed evolutionary approaches to modify the specificity and chemistry of selected enzymes. Key targets for engineering include fructose bisphosphate aldolases, which are being developed as new catalysts for stereospecific carbon-carbon bond formation. His work involves elucidating the roles of specific amino acids in the enzyme''s reaction mechanism and utilising crystallography to rationally redesign the enzyme for new substrate specificity. Additionally, directed evolution techniques, such as DNA shuffling and STEPing, are employed to create novel enzymes for biocatalysis, which are then rigorously analysed using various enzymological techniques including kinetics, ESI-MS, CD, FTIR, NMR, and X-ray crystallography. Professor Berry also investigates tagatose bisphosphate aldolase, N-acetylneuraminate lyase, and N-acetylneuraminate synthase, enzymes involved in the biosynthesis of sialic acid, which plays a crucial role in many biological recognition events. His research aims to understand the functioning of these enzymes and redesign them to serve as catalysts for the synthesis of useful analogs of sialic acid. His research is supported by the BBSRC and The Wellcome Trust.
Molecular Enzymology
Protein Engineering
Directed Evolution
Aldolases
Enzyme Specificity
Biocatalysis
Crystallography
Enzyme Kinetics
DNA Shuffling
Sialic Acid Biosynthesis
Enzyme Redesign
Enzymological Techniques
Random Mutagenesis
Site-Directed Mutagenesis
Enzyme Assays
Protein Purification
Kinetics
ESI-MS
CD
FTIR
NMR
X-ray Crystallography
Fructose Bisphosphate Aldolases
N-acetylneuraminate Lyase
N-acetylneuraminate Synthase.
Career overview
Professor Neil Ranson studied for a Biochemistry degree and subsequently completed a PhD in Mechanistic Enzymology at the University of Bristol under the supervision of Professor Tony Clarke. His doctoral research focused on understanding how the molecular chaperones GroEL and GroES assist in the folding of proteins within the crowded cellular environment. He then transitioned into structural biology, working with Professor Helen Saibil at Birkbeck College, London. Professor Ranson joined the University of Leeds as a University Research Fellow in 2002 and has progressed through roles as a Lecturer and Associate Professor to his current position as Professor of Structural Molecular Biology. He serves as the Director of The Astbury Centre for Structural Molecular Biology and the Director of Electron Microscopy at the Astbury Biostructure Laboratory.
Research interests
Professor Ranson''s research focuses on the structure of macromolecules such as proteins and nucleic acids, as well as the dynamic, heterogeneous complexes they form that drive biological function. A major area of interest is structural virology, where the lab investigates various aspects of virus structure using cryo-electron microscopy, including virus assembly, uncoating, and virus-receptor interactions. The lab is currently working on a diverse range of viral pathogens that are significant for food security and human health. Additionally, Professor Ranson''s lab maintains a strong interest in protein folding studies, exploring how proteins fold into membranes and the mechanisms of protein misfolding that lead to amyloidoses.
Career overview
Professor Michael Webb is a biological chemist with a particular interest in the emerging field of engineering biology. He obtained his PhD from the University of Cambridge, where he worked with the late Professor Chris Abell. Following this, he undertook postdoctoral research with Professor Stephen Benkovic at Penn State University and Professor Alison Smith in Plant Sciences at Cambridge. Professor Webb joined the School of Chemistry at the University of Leeds as a Lecturer in Chemical Biology in 2007, was promoted to Associate Professor in 2014, and became a Professor of Biological Chemistry in 2023. His research interests lie at the interface of biochemistry and chemistry, and he is a member of the Astbury Centre for Structural Molecular Biology.
Research interests
Professor Webb''s research interests lie at the interface of biochemistry and chemistry, with a particular focus on biosynthesis and mechanistic aspects of protein chemistry. His work has included investigations into the pathways for essential metabolites such as pantothenate (vitamin B5), thiamine (vitamin B1), purines (the building blocks of DNA), and sirohaem, with current studies concentrating on the regulation within these pathways. Recently, he has developed interests in the controlled modification of proteins, the chemical biology of phosphorylation, and the biosynthesis of natural products. Notable highlights from his research include the characterisation of a fifth protein essential for pantothenate biosynthesis in bacteria, the development of methods for quantitative N-terminal labelling of proteins, and the synthesis of stable analogues of phosphorylated histidine. His research group employs a variety of biophysical approaches, including calorimetry, macromolecular crystallography, and organic synthesis. More detailed information about recent research and current projects can be found on the group website.
Biological Chemistry
Chemical Biology
Bioorganic Chemistry
Biosynthesis
Engineering Biology
Protein Chemistry
Metabolites
Pantothenate
Thiamine
Purines
Sirohaem
Protein Modification
Chemical Biology of Phosphorylation
Natural Products
Biophysical Approaches
Calorimetry
Macromolecular Crystallography
Organic Synthesis.
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