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The structure and function of an indanomycin polyketide synthase as a tool for novel antibiotic production


Faculty of Biological Sciences

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Prof A Berry , Prof N A Ranson , Dr M E 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

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


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