Science | Martin Walsh

Martin Walsh
Structural Biology

Martin Walsh is Diamond's life science coordinator. Life sciences at Diamond currently spans a range of disciplines providing beamlines for macromolecular crystallography, small-angle X-ray scattering, circular dichroism, infrared microspectroscopy and X-ray imaging for biology as well as exploiting opportunities on other diamond beamlines and fostering interactions with the Research Complex at Harwell for which Diamond is a stakeholder.

Email: Martin Walsh
Tel: +44 (0) 1235 778518

Key Research Areas

Structural Biology of bacterial pathogens, structural proteomics, high-throughput methods for structural biology

Current Research Areas

Bacterial pathogenesis

Our research is using a targeted structural and functional approach to understanding at the molecular level how bacteria cause disease. We have focused our efforts in the main part on bacterial pathogens that continue to pose a significant health risk to the very young and elderly and have identified a number of vital processes within these pathogens to characterize and assess as targets for drug discovery. Our interests lie predominately in understanding the mechanisms used by bacterial pathogens to adhere to the host cell surfaces and the regulation of virulence. Presently we have several projects focused on understanding specific processes important to bacterial pathogenesis in three important human pathogens Streptococcus pneumoniae, Haemophilus influenzae and Pseudomonas aeruginosa:

  • Streptococcus pneumoniae is the most common cause of bacterial meningitis, community-acquired pneumonia, bacteremia and otitis media worldwide. Prevention and treatment of pneumococcal disease remains challenging due to limited availability of an effective vaccine for children, emergence of antibiotic resistance and the difficulties in detecting the many types of infection the pneumococcus causes. The image on the right illustrates some of our recent work where we determined the structure of oseltamivir carboxylate (Tamiflu) bound at the active site of neuraminidase A (nanA) of S. pneumoniae
  • Non-typeable Haemophilus influenzae (NTHI) is a benign nasopharyngeal commensal microorganism, but also an opportunistic invader of the normally sterile middle ear space. As such, NTHI predominates in both chronic otitis media (OM). As for Streptococcus pneumoniae NTHI strains principally have a role in other localized respiratory diseases such as acute sinusitis, community-acquired pneumonia and have important consequences in patients with chronic obstructive pulmonary diseases and cystic fibrosis.
  
Crystals of a virulence factor from NTHI
  • Pseudomonas aeruginosa is an opportunistic, nosocomial pathogen that typically infects the pulmonary and urinary tract and a variety of systemic infections, particularly in patients with severe burns and patients who are immunosuppressed. In addition cystic fibrosis patients are characteristically susceptible to chronic infection by P. aeruginosa. It is the most common pathogen isolated from short-stay hospitalized patients and due to the emergence of multi-drug resistance strains has become a significant public health problem.

Identification and validation of potential targets for the development of novel antimicrobials to combat the emergence of multidrug resistance strains of these pathogens is the ultimate aim of the research.

High-throughput methods for structural biology

The SPINE standard sample holder
The SPINE standard sample holder

At the end of the 1990’s as structural genomics programs were getting off the ground, attention began to be focused on reducing the manual effort involved in collecting X-ray diffraction data and improving the efficiency of use of the available synchrotron beamtime. Synchrotron groups worldwide started concerted development programs aimed at providing high-throughput, semi- and fully-automatic platforms for data collection at beamlines. We have contributed to these efforts through the development of hardware and software to aid automation of diffraction experiments. Work has focused on delivering sample automation through the use of robotics and associated software such as ISPyB where our efforts have been primarily supported through the BBSRC e-SCIENCE initiative e-HTPX and grants from the MRC as well as through European Union grants such as SPINE and BioXHIT. See publications 2,12, 14 and 15 for full details.

Publications since 2004

  1. Gut, H., Xu, G., Taylor, G. L. & Walsh, M. A. Structural basis for Streptococcus pneumoniae NanA inhibition by influenza antivirals zanamivir and oseltamivir carboxylate. J Mol Biol 409, 496-503, doi:S0022-2836(11)00431-1 [pii] 10.1016/j.jmb.2011.04.016 (2011).
  2. Gabadinho, J. et al. MxCuBE: a synchrotron beamline control environment customized for macromolecular crystallography experiments. Journal of Synchrotron Radiation 17, 700-707, doi:doi:10.1107/S0909049510020005 (2010).
  3. Cheng, Z. et al. Structural basis of the sensor-synthase interaction in autoinduction of the quorum sensing signal DSF biosynthesis. Structure 18, 1199-1209, doi:S0969-2126(10)00263-7 [pii] 10.1016/j.str.2010.06.011 (2010).
  4. Loh, P. G. et al. Structural basis for translational inhibition by the tumour suppressor Pdcd4. EMBO J 28, 274-285, doi:emboj2008278 [pii] 10.1038/emboj.2008.278 (2009).
  5. Flannery, D. et al. in Fifth IEEE Intnl. Conference on e-science. 201-207.
  6. Fang, F. et al. Allelic variation of bile salt hydrolase genes in Lactobacillus salivarius does not determine bile resistance levels. J Bacteriol 191, 5743-5757, doi:JB.00506-09 [pii] 10.1128/JB.00506-09 (2009).
  7. Rossi, F., Garavaglia, S., Montalbano, V., Walsh, M. A. & Rizzi, M. Crystal structure of human kynurenine aminotransferase II, a drug target for the treatment of schizophrenia. J Biol Chem 283, 3559-3566, doi:M707925200 [pii] 10.1074/jbc.M707925200 (2008).
  8. Oke, M. et al. Unusual chromophore and cross-links in ranasmurfin: a blue protein from the foam nests of a tropical frog. Angew Chem Int Ed Engl 47, 7853-7856, doi:10.1002/anie.200802901 (2008).
  9. Ling, S. H. et al. Crystal structure of human Edc3 and its functional implications. Mol Cell Biol 28, 5965-5976, doi:MCB.00761-08 [pii] 10.1128/MCB.00761-08 (2008).
  10. Gut, H., King, S. J. & Walsh, M. A. Structural and functional studies of Streptococcus pneumoniae neuraminidase B: An intramolecular trans-sialidase. FEBS Lett 582, 3348-3352, doi:S0014-5793(08)00713-8 [pii] 10.1016/j.febslet.2008.08.026 (2008).
  11. Deshpande, A., Wang, S., Walsh, M. A. & Dokland, T. Structure of the equine arteritis virus nucleocapsid protein reveals a dimer-dimer arrangement. Acta Crystallographica Section D: Biological Crystallography 63, 581-586 (2007).
  12. Rosenbaum, G. et al. The Structural Biology Center 19ID undulator beamline: Facility specifications and protein crystallographic results. Journal of Synchrotron Radiation 13, 30-45 (2006).
  13. McMahon, S. A. et al. Crystallization of Ranasmurfin, a blue-coloured protein from Polypedates leucomystax. Acta Crystallographica Section F: Structural Biology and Crystallization Communications 62, 1124-1126 (2006).
  14. Cipriani, F. et al. Automation of sample mounting for macromolecular crystallography. Acta Crystallographica Section D: Biological Crystallography 62, 1251-1259 (2006).
  15. Beteva, A. et al. High-throughput sample handling and data collection at synchrotrons: Embedding the ESRF into the high-throughput gene-to-structure pipeline. Acta Crystallographica Section D: Biological Crystallography 62, 1162-1169 (2006).
  16. Salgado, P. S., Walsh, M. A., Laurila, M. R. L., Stuart, D. I. & Grimes, J. M. Going soft and SAD with manganese. Acta Crystallographica Section D: Biological Crystallography 61, 108-111 (2005).
  17. Meier, C. et al. Overcoming the false-minima problem in direct methods: Structure determination of the packaging enzyme P4 from bacteriophage ?13. Acta Crystallographica Section D: Biological Crystallography 61, 1238-1244 (2005).
  18. Chen, N., Walsh, M. A., Liu, Y., Parker, R. & Song, H. Crystal structures of human DcpS in ligand-free and m7GDP-bound forms suggest a dynamic mechanism for scavenger mRNA decapping. Journal of Molecular Biology 347, 707-718 (2005).
  19. Van Den Heuvel, R. H. H. et al. Structural Studies on Flavin Reductase PheA2 Reveal Binding of NAD in an Unusual Folded Conformation and Support Novel Mechanism of Action. Journal of Biological Chemistry 279, 12860-12867 (2004).
  20. Sutton, G. et al. The nsp9 Replicase Protein of SARS-Coronavirus, Structure and Functional Insights. Structure 12, 341-353 (2004).
  21. Lo Surdo, P., Walsh, M. A. & Sollazzo, M. A novel ADP- and zinc-binding fold from function-directed in vitro evolution. Nature Structural and Molecular Biology 11, 382-383 (2004).
  22. Lartigue, A. et al. Sulfur Single-wavelength Anomalous Diffraction Crystal Structure of a Pheromone-Binding Protein from the Honeybee Apis mellifera L. Journal of Biological Chemistry 279, 4459-4464 (2004).
  23. Kong, C. et al. Crystal structure and functional analysis of the eukaryotic class II release factor eRF3 from S. pombe. Molecular Cell 14, 233-245 (2004).
  24. Kainov, D. E. et al. Crystallization and preliminary X-ray diffraction analysis of bacteriophage ?12 packaging factor P7. Acta Crystallographica Section D: Biological Crystallography 60, 2368-2370 (2004).
  25. Dottorini, T., Vaughan, C. K., Walsh, M. A., LoSurdo, P. & Sollazzo, M. Crystal Structure of a Human VH: Requirements for Maintaining a Monomeric Fragment. Biochemistry 43, 622-628 (2004).
  26. Dokland, T. et al. West Nile virus core protein: Tetramer structure and ribbon formation. Structure 12, 1157-1163 (2004).

Research Group Members

  • Domenico Bellini (PDRA)
  • Petra Lukacik (PDRA)
  • Andrea Gumiero (PDRA)
  • Victoria Arena (PhD student)
  • Julie Thye (PhD student)

Current Funding