Biomolecular Interactions

Bioscience Embedded within Chemistry - Group Coordinator (2024/25): Prof Jonathan Heddle

Biomolecular interactions, including contacts between biological macromolecules (protein/protein or protein/nucleic acids) and protein-ligand interactions are central to biochemistry. This grouping addresses fundamental questions concerning, for example, the recognition of DNA by bacterial proteins, the biophysical basis of allostery and the supply of metals to proteins. Multiple projects aim to identify targets for new antimicrobial (and antiviral) compounds and typically exploit a wide range of chemical, biochemical, and biophysical methods.

More than half of the members of the group are located in embedded biology laboratories within the Department of Chemistry and PIs have close interactions with the Bioactive Chemistry and Synthesis grouping in Chemistry.

Affiliated Members:

Prof Adam Benham, Prof P Chazot, Prof Tony Fawcett, Dr Martin Goldberg, Prof Keith Lindsey, Dr J Liu, Prof David Weinkove

Recent Publications

Thomas Cummins, Suraj Songra, Stephen R. Garrett, Tim R. Blower, Giuseppina Mariano. (2024) Multi-conflict islands are a widespread trend within Serratia spp. Cell Reports

Xibing Xu, Roland Barriot, Bertille Voisin, Tom J. Arrowsmith, Ben Usher, Claude Gutierrez, Xue Han, Carine Pagès, Peter Redder, Tim R. Blower, Olivier Neyrolles & Pierre Genevaux. (2024) Nucleotidyltransferase toxin MenT extends aminoacyl acceptor ends of serine tRNAs to control Mycobacterium tuberculosis growth Nature Communications

Mina, J.G., Parthasarathy, P., Porta, E.O., Denny, P.W.,  (2024) Kalesh, K. BONCAT-iTRAQ Labelling Reveals Molecular Markers of Adaptive Responses in Toxoplasma gondii to Pyrimethamine Treatment Pathogens

Arrowsmith, Tom J.; Xu, Xibing; Xu, Shangze; Usher, Ben; Stokes, Peter; Guest, Megan; Bronowska, Agnieszka K.; Genevaux, Pierre; Blower, Tim R. (2024) Inducible auto-phosphorylation regulates a widespread family of nucleotidyltransferase toxins Nature Communications

Alpizar-Sosa, Edubiel A.; Zimbres, Flavia M.; Mantilla, Brian S.; Dickie, Emily A.; Wei, Wenbin; Burle-Caldas, Gabriela A.; Filipe, Laura N.S.; Van Bocxlaer, Katrien; Price, Helen P.; Ibarra-Meneses, Ana V.; Beaudry, Francis; Fernandez-Prada, Christopher; Whitfield, Philip D.; Barrett, Michael P.; Denny, Paul W (2024) Evaluation of the Leishmania inositol phosphorylceramide synthase as a drug target using a chemical and genetic approach ACS Infectious Diseases

Abdullayev, Elshan; Paterson, Joy R.; Kuszynski, Eleanor P.; Hamidi, M. Daud; Nahar, Papreen; Greenwell, H. Chris; Neumann, Anke; Sharples, Gary J. (2024) Evaluation of the antibacterial properties of commonly used clays from deposits in central and southern Asia Clays and Clay Minerals

Sam C. Went, David M. Picton, Richard D. Morgan, Andrew Nelson, Aisling Brady, Giuseppina Mariano, David T. F. Dryden, Darren L. Smith, Nicolas Wenner, Jay C. D. Hinton & Tim R. Blower. (2024) Structure and rational engineering of the PglX methyltransferase and specificity factor for BREX phage defence Nature Communications

Koutsogiannis, Zisis; Denny, Paul W. (2024) Rapid genotyping of Toxoplasma gondii isolates via Nanopore-based multi-locus sequencing AMB Express

Birkholz, Nils; Kamata, Kotaro; Feussner, Maximilian; Wilkinson, Max E.; Cuba Samaniego, Christian; Migur, Angela; Kimanius, Dari; Ceelen, Marijn; Went, Sam C.; Usher, Ben; Blower, Tim R.; Brown, Chris M.; Beisel, Chase L.; Weinberg, Zasha; Fagerlund, Robert D.; Jackson, Simon A.; Fineran, Peter C. (2024) Phage anti-CRISPR control by an RNA- and DNA-binding helix–turn–helix protein Nature 

Ridgway, Rachel; Lu, Hanshuo; Blower, Tim R.; Evans, Nicholas James; Ainsworth, Stuart (2024) Genomic and taxonomic evaluation of 38 Treponema prophage sequences BMC Genomics

Agapov, Aleksei; Baker, Kate; Bedekar, Paritosh; Bhatia, Rama; Blower, Tim R.; Brockhurst, Michael A.; Brown, Cooper; Chong, Charlotte; Fothergill, Joanne L.; Graham, Shirley; Hall, James P. J.; Maestri, Alice; McQuarrie, Stuart; Olina, Anna; Pagliara, Stefano; Recker, Mario; Richmond, Anna; Shaw, Steven J.; Szczelkun, Mark D.; Taylor, Tiffany B.; van Houte, Stineke; Went, Sam C.; Westra, Edze R.; White, Malcolm F.; Wright, Rosanna. (2024) Multi-layered genome defences in bacteria Current Opinion in Microbiology

Blower, T. R., & van Houte, S. (2023). Viruses wrap up bacterial defence systems. Nature

Bandak, A. F., Blower, T. R., Nitiss, K. C., Shah, V., Nitiss, J., & Berger, J. (2023). Using energy to go downhill—a genoprotective role for ATPase activity in DNA topoisomerase II. Nucleic Acids Research

Beck, I. N., Arrowsmith, T. J., Grobbelaar, M. J., Bromley, E. C., Marles-Wright, J., & Blower, T. R. (2023). Toxin release by conditional remodelling of ParDE1 from Mycobacterium tuberculosis leads to gyrase inhibition. Nucleic Acids Research

Paterson, J. R., Wadsworth, J. M., Hu, P., & Sharples, G. J. (2023). A critical role for iron and zinc homeostatic systems in the evolutionary adaptation of Escherichia coli to metal restriction.

Hong Y, Mackenzie ES, Firth SJ, Bolton JRF, Stewart LJ, Waldron KJ, Djoko KY. (2023) Mis-regulation of Zn and Mn homeostasis is a key phenotype of Cu stress in Streptococcus pyogenes. Metallomics. 

Zisis Koutsogiannis, John G. Mina, Christin A. Albus, Matthijs A. Kol, Joost C. M. Holthuis, Ehmke Pohl, Paul W. Denny. (2023) Toxoplasma ceramide synthases: Gene duplication, functional divergence, and roles in parasite fitness The FASEB Journal

Waite R, Adams CT, Chisholm DR, Sims CHC, Hughes JG, Dias E, White EA, Welsby K, Botchway SW, Whiting A, Sharples GJ, Ambler CA. (2023) The antibacterial activity of a photoactivatable diarylacetylene against Gram-positive bacteria. Frontiers in Microbiology

Wan Omar WH, Mahyudin NA, Azmi NN, Mahmud Ab Rashid NK, Ismail R, Mohd Yusoff MHY, Khairil Mokhtar NF, Sharples GJ. (2023) Effect of natural antibacterial clays against single biofilm formation by Staphylococcus aureus and Salmonella Typhimurium bacteria on a stainless-steel surface. International Journal of Food Microbiology. 

Nailma S A Dos Santos, Carlos F. Estevez-Castro, Juan P. Macedo, Daniela F. Chame, Thiago Castro-Gomes, Mariana Santos-Cardoso, Gabriela A. Burle-Caldas,  Courtney N. Covington, Patrick G. Steel, Terry K. Smith, Paul W. Denny, Santuza M. R. Teixeira (2023) Disruption of the inositol phosphorylceramide synthase gene affects Trypanosoma cruzi differentiation and infection capacity PLOS Neglected Tropical Diseases 

Basak, P., Cabelli, D. E., Chivers, P. T., Farquhar, E. R., & Maroney, M. J. (2023) In vitro maturation of NiSOD reveals a role for cytoplasmic histidine in processing and metalation. Metallomics

Kelly, A., Went, S. C., Mariano, G., Shaw, L. P., Picton, D. M., Duffner, S. J., Blower, T. R. (2023). Diverse Durham collection phages demonstrate complex BREX defence responses. Applied and Environmental Microbiology

Ani Paloyan, Armen Sargsyan, Mariam D. Karapetyan, Artur Hambardzumyan, Sergei Kocharov, Henry Panosyan, Karine Dyukova, Marina Kinosyan, Anna Krueger, Cecilia Piergentili, Will A. Stanley, Karrera Y. Djoko, Arnaud Baslé, Jon Marles-Wright, Garabed Antranikian (2023) 'Structural and biochemical characterisation of the N-carbamoyl-β-alanine amidohydrolase from Rhizobium radiobacter MDC 8606' The FEBS Journal

Xu, X., Usher, B., Gutierrez, C., Barriot, R., Arrowsmith, T. J., Han, Xue., Redder, Peter, Neyrolles, Olivier, Blower, Tim R, Genevaux, P. (2023). MenT nucleotidyltransferase toxins extend tRNA acceptor stems and can be inhibited by asymmetrical antitoxin binding. Nature Communications

Djoko Y. Karrera. (2023) Control of nutrient metal availability during host-microbe interactions: beyond nutritional immunity JBIC Journal of Biological Inorganic Chemistry

Atreyee Mishra, Karrera Y. Djoko, Yi-Hsuan Lee, Rianne M. Lord, Grace Kaul, Abdul Akhir, Deepanshi Saxena, Sidharth Chopra and James W. Walton. (2023) Water-soluble copper pyrithione complexes with cytotoxic and antibacterial activity  Organic & Biomolecular Chemistry

Stewart, L. J., Hong, Y., Holmes, I. R., Firth, S. J., Ahmed, Y., Quinn, J., …Djoko, K. Y. (2023). Salivary Antimicrobial Peptide Histatin-5 Does Not Display Zn(II)-Dependent or -Independent Activity against Streptococci. ACS Infectious Diseases

Tsai, Ming-Han C.; Caswell, Sarah J.; Morris, Elizabeth R.; Mann, Melanie C.; Pennell, Simon; Kelly, Geoff; Groom, Harriet C.T.; Taylor, Ian A.; Bishop, Kate N. (2023) 'Attenuation of reverse transcriptase facilitates SAMHD1 restriction of HIV-1 in cycling cells' Retrovirology

Mariano, G. and Blower, T.R. (2023) 'Conserved domains can be found across distinct phage defence systems.', Molecular Microbiology 

Kelly, A. and Arrowsmith, T.J. and Went, S.C. and Blower, T.R. (2023) 'Toxin–antitoxin systems as mediators of phage defence and the implications for abortive infection.', Current Opinion in Microbiology,

Macdonald, E. and Wright, R. and Connolly, J. P. R. and Strahl, H. and Brockhurst, M. and van Houte, S. and Blower, T. R. and Palmer, T. and Mariano, G. (2023) 'The novel anti-phage system Shield co-opts an RmuC domain to mediate phage defense across Pseudomonas species.', PLOS Genetics

Bandak, A. F. and Blower, T. R. and Nitiss, K. C. and Gupta, R. and Lau, A. Y. and Guha, R. and Nitiss, J. L. and Berger, J. M. (2023) Naturally mutagenic sequence diversity in a human type II topoisomerase.', Proceedings of the National Academy of Sciences

Gannon, Harry G. and Cann, Martin J. (2023) Near atmospheric carbon dioxide activates plant ubiquitin cross-linking. BBA Advances

Young, Tessa R. and Deery, Evelyne and Foster, Andrew W. and Martini, Maria Alessandra and Osman, Deenah and Warren, Martin J. and Robinson, Nigel J. (2023) Two Distinct Thermodynamic Gradients for Cellular Metalation of Vitamin B12., JACS Au 

Petit, Guillaume A. and Hong, Yaoqin and Djoko, Karrera Y. and Whitten, Andrew E. and Furlong, Emily J. and McCoy, Airlie J. and Gulbis, Jacqueline M. and Totsika, Makrina and Martin, Jennifer L. and Halili, Maria A. (2022) The suppressor of copper sensitivity protein C from Caulobacter crescentus is a trimeric disulfide isomerase that binds copper(I) with subpicomolar affinity. Acta Crystallographica Section D Structural Biology

O’Hern, Charlotte I. Z. and Djoko, Karrera Y. (2022) Copper Cytotoxicity: Cellular Casualties of Noncognate Coordination Chemistry. mBio

Paterson JR, Beecroft MS, Mulla RS, Osman D, Reeder NL, Caserta JA, Young TR, Pettigrew CA, Davies GE, Williams JAG, Sharples GJ. (2022) Insights into the Antibacterial Mechanism of Action of Chelating Agents by Selective Deprivation of Iron, Manganese, and Zinc. Applied and Environmental Microbiology. 

Brouwer, Stephan and Jespersen, Magnus G. and Ong, Cheryl-lynn Y. and De Oliveira, David M. P. and Keller, Bernhard and Cork, Amanda J. and Djoko, Karrera Y. and Davies, Mark R. and Walker, Mark J. (2022) 'Streptococcus pyogenes Hijacks Host Glutathione for Growth and Innate Immune Evasion.  mBio

Djoko, Karrera and Cavet, Jennifer (2022) Perspectives on Metals in Microbiology Perspectives on Metals in Microbiology, Microbiology

Guillen-Garcia, A. and Gibson, S. and Jordan, C. and Ramaswamy, V. and Linthwaite, V. and Hodgson, D. and Blower, T. and Verlet, J. and Degiacomi, M. and Palsson, L-O. and Cann, M.J. (2022) Allophycocyanin A is a carbon dioxide receptor in the cyanobacterial phycobilisome. Nature Communications

Alpizer-Sosa, E.A., Ithnin, N.R.B., Pountain, A.W., Weidt, A.K., Donachie, A.M., Ritchie, R., Dickie, E.A., Burchmore, R.J.S., Denny, P.W., Barrett, M.P. (2022). Amphotericin B resistance in Leishmania mexicana: Alterations to sterol metabolism and oxidative stress response. PLOS Neglected Tropical Disease

Alpizar-Sosa, E.A., Kumordzi, Y., Wei, W., Whitfield, P., Barrett, M.P., Denny, P.W. (2022). Genome deletions to overcome the directed loss of gene function in Leishmania. Frontiers in Cellular and Infection Microbiology. 

Katy A S Cornish, Joanna Lange, Arnthór Aevarsson, Ehmke Pohl (2022). CPR-C4 is a highly conserved novel protease from the Candidate Phyla Radiation with remote structural homology to human vasohibins. Journal of Biological Chemistry

David M Picton, Joshua D Harling-Lee, Samuel J Duffner, Sam C Went, Richard D Morgan, Jay C D Hinton, Tim R Blower (2022). A widespread family of WYL-domain transcriptional regulators co-localizes with diverse phage defence systems and islands. Nucleic Acids Research Volume 50, Issue 9, 20 May 2022, Pages 5191–5207

Elise M.Ling, Arnaud Baslé, Ian G.Cowell, Bertvan den Berg, Tim R.Blower, Caroline A.Austin. (2022). A comprehensive structural analysis of the ATPase domain of human DNA topoisomerase II beta bound to AMPPNP, ADP, and the bisdioxopiperazine, ICRF193. Structure

Izaak N. Beck, David M.Picton, Tim R.Blower (2022). Crystal structure of the BREX phage defence protein BrxA. Current Research in Structural Biology, Volume 4.

Douglas O Escrivani, Rebecca L Charlton, Marjolly B Caruso, Gabriela A Burle-Caldas, Maria Paula G Borsodi, Russolina B Zingali, Natalia Arruda-Costa, Marcos V Palmeira-Mello, Jéssica B de Jesus, Alessandra M T Souza, Bárbara Abrahim-Vieira, Stefanie Freitag-Pohl, Ehmke Pohl, Paul W Denny, Bartira Rossi-Bergmann, Patrick G Steel (2021). Chalcones identify cTXNPx as a potential antileishmanial drug target. PLOS Negelcted Tropical Diseases.

Azmi NN, Mahyudin NA, Wan Omar WH, Mahmud Ab Rashid NK, Ishak CF, Abdullah AH, Sharples GJ. (2021) Antibacterial Activity of Clay Soils against Food-Borne Salmonella typhimurium and Staphylococcus aureus. Molecules. 

Picton, D.M., Luyten, Y.A., Morgan, R.D., Nelson, A., Smith, D.L., Dryden, D.T.F., Hinton, J.C.D. & Blower, T.R. (2021). The phage defence island of a multidrug resistant plasmid uses both BREX and type IV restriction for complementary protection from viruses. Nucleic Acids Research

Cox HJ, Li J, Saini P, Paterson JR, Sharples GJ, Badyal JPS. (2021) Bioinspired and eco-friendly high efficacy cinnamaldehyde antibacterial surfaces. Journal of Materials Chemistry B. 

Linthwaite, V.L. and Pawloski, W. and Pegg, H.B. and Townsend, P.D. and Thomas, M.J. and Brown, A.P. and Hodgson, D.R.W. and Lorimer, G.H. and Fushman, D. and Cann, M.J. (2021) Ubiquitin is a carbon dioxide-binding protein., Science advances., 7 . eabi5507.

Usher, B. and Birkholz, N. and Beck, I.N. and Fagerlund, R.D. and Jackson, S.A. and Fineran, P.C. and Blower, T.R. (2021) Crystal structure of the anti-CRISPR repressor Aca2., Journal of Structural Biology, 213 (3). p. 107752.

Nijjar, Sarbjit and Maddison, Daniel and Meigh, Louise and Wolf, Elizabeth and Rodgers, Thomas and Cann, Martin and Dale, Nicholas (2021) Opposing modulation of Cx26 gap junctions and hemichannels by CO2., Journal of physiology, 599 (1). pp. 103-118.

Mina, John G. M., Charlton, Rebecca L., Alpizar-Sosa, Edubiel, Escrivani, Douglas O., Brown, Christopher, Alqaisi, Amjed, Borsodi, Maria Paula G., Figueiredo, Claudia P., de Lima, Emanuelle V., Dickie, Emily A., Wei, Wenbin, Coutinho-Silva, Robson, Merritt, Andy, Smith, Terry K., Barrett, Michael P., Rossi-Bergmann, Bartira, Denny, Paul W. & Steel, Patrick G. (2021). Antileishmanial Chemotherapy through Clemastine Fumarate Mediated Inhibition of the Leishmania Inositol Phosphorylceramide Synthase. ACS Infectious Diseases 7(1): 47-63

Tomlinson, Charles W. E., Cornish, Katy A. S., Whiting, Andrew & Pohl, Ehmke (2021). Structure-functional relationship of cellular retinoic acid binding proteins I and II interacting with natural and synthetic ligands. Acta Crystallographica Section D 77(2): 164-175.

Young, T.R., Martini, M.A., Foster, A.W., Glasfeld, A., Osman, D., Morton, R.J., Deery, E., Warren, M.J., Robinson, N.J. (2021) Calculating metalation in cells reveals CobW acquires Co^II for vitamin B₁₂ biosynthesis while related proteins prefer Zn^II. Nature Communications, 12: 1195 (1-15).

Cai, Y., Usher, B., Gutierrez, C., Tolcan, A., Mansour, M., Fineran, P.C., Condon, C., Neyrolles, O., Genevaux, P. & Blower, T.R. (2020). A nucleotidyltransferase toxin inhibits growth of Mycobacterium tuberculosis through inactivation of tRNA acceptor stems. Science Advances 6(31): eabb6651.

Stewart, Louisa J., Ong, Cheryl-lynn Y., Zhang, May M., Brouwer, Stephan, McIntyre, Liam, Davies, Mark R., Walker, Mark J., McEwan, Alastair G., Waldron, Kevin J. & Djoko, Karrera Y. (2020). Role of Glutathione in Buffering Excess Intracellular Copper in Streptococcus pyogenes. mBio 11(6): e02804-20.

Brown, Max, Dainty, Samantha, Strudwick, Natalie, Mihai, Adina D., Watson, Jamie N., Dendooven, Robina, Paton, Adrienne W., Paton, James C. & Schröder, Martin (2020). Endoplasmic reticulum stress causes insulin resistance by inhibiting delivery of newly synthesised insulin receptors to the cell surface. Molecular Biology of the Cell 31(23): 2495-2629.

Sharples, Gary J., Heddle, Jonathan G., Kozak, Maciej, Taube, Michał, Hughes, Timothy R, Pålsson, Lars-Olof, Bowers, Laura Y., Curtis, Fiona A., Plewka, Jacek, Świątek, Sylwia, Paterson, Joy R., Jolma, Arttu, Yang, Ally W.H., Gittens, William H., Trotter, Alexander J., Balakrishnan, Dhanasekaran & Chakraborti, Soumyananda (2020). A bacteriophage mimic of the bacterial nucleoid-associated protein Fis. Biochemical Journal 477(7): 1345-1362

Blower, T.R., Bandak, A., Lee, A.S.Y., Austin, C.A., Nitiss, J.L. & Berger, J.M. (2019). A complex suite of loci and elements in eukaryotic type II topoisomerases determine selective sensitivity to distinct poisoning agents. Nucleic Acids Research 47(15): 8163-8179.

Osman, D., Martini, M., Foster, A.W., Chen, J., Scott, A.J.P., Morton, R.J., Steed, J.W., Lurie-Luke, E., Huggins, T.G., Lawrence, A.D., Deery, E., Warren, M.J., Chivers, P.T., Robinson, N.J. (2019) Bacterial sensors define intracellular free energies for correct enzyme metalation. Nature Chemical Biology, 15: 241–249.

Linthwaite, V.L. and Janus, J.M. and Brown, A.P. and Wong-Pascua, D. and O’Donoghue, A.C. and Porter, A. and Treumann, A. and Hodgson, D.R.W. and Cann, M.J. (2018) The identification of carbon dioxide mediated protein post-translational modifications., Nature communications., 9 . p. 3092.

Townsend, P.D. and Dixon, C.H. and Slootweg, E.S. and Sukarta, O.C.A. and Yang, A.W.H. and Hughes, T.R. and Sharples, G.J. and Palsson, L-O. and Takken, F.L.W. and Goverse, A. and Cann, M.J. (2018) The intracellular immune receptor Rx1 regulates the DNA-binding activity of a Golden2-like transcription factor., Journal of biological chemistry., 293 (9). pp. 3218-3233.

Moore, S. and Sowa, S. and Schuchardt, C. and Deery, E. and Lawrence, A. and Ramos, J. and Billig, S. and Birkemeyer, C. and Chivers, P. and Howard, J. and Rigby, S. and Layer, G. and Warren, M. (2017) Elucidation of the biosynthesis of the methane catalyst coenzyme F430., Nature., 543 (7643). pp. 78-82.

Marsh, James W., Djoko, Karrera Y., McEwan, Alastair G. & Huston, Wilhelmina M. (2017). Copper(II)-bis(thiosemicarbazonato) complexes as anti-chlamydial agents. Pathogens and Disease 75(7): ftx084.