Dr Sheena McGowan - Researcher Profile

OMC

Address

Department of Biochemistry & Molecular Biology
Faculty of Medicine, Nursing & Health Sciences, Clayton

Contact Details

Tel: +61 3 990 29309

Fax: +61 3 990 29500

Email: Sheena.McGowan@monash.edu


Biography

Sheena McGowan was formally trained in Microbiology, completing her PhD in 2004. During her PhD she studied the structure and function of a toxin regulator from the causative agent of gas gangrene, developing what would become a long-standing interest in structure and function of proteins. During her post-doctoral work she was trained in protein crystallography and biophysics and she now applies these skills in Microbiology and Structural Biology to investigate novel methods for microbial disease control.

The McGowan laboratory is interested in characterising novel molecular drug targets. The lab has a strong research focus in the design of novel anti-malarial drugs as well as other parasitic and bacterial diseases. Primarily we are a structural biology laboratory using techniques in X-ray crystallography, biochemistry and biophysics to analyse our proteins of interest. We use this mechanistic information to design inhibitors or analogues with potential applications in human medicine.

Dr Sheena McGowan is unravelling the proteins which malaria parasites need to survive, which could lead to a new generation of therapeutic drugs.

Because at present malaria is not endemic to Australia, we tend to forget what a devastating disease it is—responsible for more than half a million deaths a year, and putting half the world’s population at risk. But for Dr Sheena McGowan, malaria remains front and centre.


The ARC Future Fellow and Monash University structural biologist is excited about the prospects for three proteins whose structures she has unravelled. She thinks they may be the targets for a new generation of therapeutic drugs to be used against the malaria parasite.

As a researcher, Sheena McGowan is unusual in that, as soon as she finished her PhD in microbiology, she switched to biochemistry— more specifically, structural biology. “I wanted to know what things looked like, how they worked.” And in the world of microbiology, that inevitably leads to protein structures.
“My discipline change was a little unusual, but I believe it makes me look at a bigger picture. I can go back and see what a protein structure means in terms of the bug that causes disease. I’m very grounded in context.”

But it has taken her nearly seven years—six of them working with Prof James Whisstock—to master what she needed to strike out on her own. Now, with the help of a Future Fellowship, she has done just that. “For me, the Future Fellowship created my independent laboratory. That was the salary I needed. And the money for consumables that went with it basically allowed me to set up my lab, to pay the bills for the students I wanted to get in and the experiments we were doing.”

The malaria story grew out of her association with Prof Whisstock. Sheena has had a long-term interest in proteases, the enzymes that break down proteins. “They are like PacMan, and essential to all aspects of life.” One evening at a conference Whisstock met a malaria researcher—now a collaborator in the project—who was looking for someone to provide structures for the three target proteins, all proteases produced by the malaria parasite. Not only did Sheena accept the challenge, but she had the first structure worked out within 12 months

Two of the three proteins are absolutely critical to the survival of the malaria parasite, says Sheena. “If you knock either of them out, the parasite dies.” They are both involved in the digestion of the blood’s oxygen carrier, haemoglobin, on which the parasite depends for food. One of them also plays an important role early in parasite development, she says. The third protein may also be essential, although that is not yet proven. Certainly, blocking its action is debilitating.
Once you have a protein structure, you can work on making molecules to inhibit its action. And in this case,

Sheena says, even though the proteins have very different structures, the active sites of all three are built around metal ions.  “For that reason, we think it might be possible to come up with a compound to inhibit all three. And that would significantly lower the rate at which the parasite could develop resistance.”
Now that she and her team have determined structure of two of the proteins, they are faced with another interesting question. “These are really big proteases. Huge. In terms of an efficient parasite, like malaria, why bother to make such a huge molecule which is essential, when you could probably get something that works as well in a smaller version.”

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Qualifications

PHD (MICROBIOLOGY)
Institution: Monash University
Year awarded: 2004
BSC(BIOMEDICAL) (HONOURS)
Institution: Monash University
Year awarded: 2000
BSC (BIOMEDICAL)
Institution: Monash University
Year awarded: 1999

Publications

Book Chapters

Grigoryev, S., McGowan, S., 2011, Isolation and characterization of the nuclear serpin MENT, in Methods in Enzymology, Volume 501: Serpin Structure and Evolution, eds James C Whisstock and Phillip I Bird, Academic Press, USA, pp. 29-47.

Zhang, Q., Law, R.H.P., Buckle, A.M., Cabrita, L., McGowan, S., Irving, J.A., Faux, N.G., Lesk, A.M., Bottomley, S.P., Whisstock, J., 2007, Serpins in Prokaryotes, in Molecular and Cellular Aspects of the Serpinopathies and Disorders in Serpin Activity, eds G.A. Silverman & D.A. Lomas, World Scientific, Singapore, pp. 131-162.

Cheung, K.J., McGowan, S., Rood, J.I., 2005, Two-component signal transduction systems in Clostridia, in Handbook on Clostridia, eds Peter Duerre, CRC Press, Boca Raton USA, pp. 545-560.

Journal Articles

Poreba, M., McGowan, S., Skinner-Adams, T.S., Trenholme, K.R., Gardiner, D.L., Whisstock, J.C., To, J., Salvesen, G.S., Dalton, J.P., Drag, M., 2012, Fingerprinting the substrate specificity of M1 and M17 aminopeptidases of human malaria, Plasmodium falciparum, PLoS ONE [P], vol 7, issue 2 (Art. ID: e31938), Public Library of Science, USA, pp. 1-8.

Sivaraman, K.K., Oellig, C.A., Huynh, K., Atkinson, S.C., Poreba, M., Perugini, M.A., Trenholme, K.R., Gardiner, D.L., Salvesen, G., Drag, M., Dalton, J.P., Whisstock, J.C., McGowan, S., 2012, X-ray crystal structure and specificity of the Plasmodium falciparum malaria aminopeptidase PfM18AAP, Journal of Molecular Biology [P], vol 422, issue 4, Academic Press, UK, pp. 495-507.

McGowan, S., Buckle, A.M., Mitchell, M.S., Hoopes, J.T., Gallagher, D.T., Heselpoth, R.D., Shen, Y., Reboul, C.F., Law, R.H., Fischetti, V.A., Whisstock, J.C., Nelson, D.C., 2012, X-ray crystal structure of the streptococcal specific phage lysin PlyC, Proceedings Of The National Academy Of Sciences Of The United States Of America [P], vol 109, issue 31, National Academy of Sciences, USA, pp. 12752-12757.

Harbut, M., Velmourougane, G., Dalal, S., Reiss, G., Whisstock, J., Onder, O., Brisson, D., McGowan, S., Klemba, M., Greenbaum, D., 2011, Bestatin-based chemical biology strategy reveals distinct roles for malaria M1- and M17-family aminopeptidases, Proceedings Of The National Academy Of Sciences Of The United States Of America [P], vol 108, issue 34, National Academy of Sciences, USA, pp. E526-E534.

Velmourougane, G., Harbut, M.B., Dalal, S., McGowan, S., Oellig, C., Meinhardt, N., Whisstock, J.C., Klemba, M., Greenbaum, D.C., 2011, Synthesis of new (-)-bestatin-based inhibitor libraries reveals a novel binding mode in the S1 pocket of the essential malaria M1 metalloaminopeptidase, Journal of Medicinal Chemistry [P], vol 54, issue 6, American Chemical Society, USA, pp. 1655-1666.

Winter, K.L., Isbister, G.K., McGowan, S., Konstantakopoulos, N., Seymour, J.E., Hodgson, W.C., 2010, A pharmacological and biochemical examination of the geographical variation of Chironex fleckeri venom, Toxicology Letters [P], vol 192, Elsevier Ireland Ltd, Ireland, pp. 419-424.

Skinner-Adams, T.S., Stack, C.M., Trenholme, K.R., Brown, C.L., Grembecka, J., Lowther, J., Mucha, A., Drag, M., Kafarski, P., McGowan, S., Whisstock, J., Gardiner, D.L., Dalton, J.P., 2010, Plasmodium falciparum neutral aminopeptidases: new targets for anti-malarials, Trends In Biochemical Sciences [P], vol 35, Elsevier Ltd, UK & Switzerland, pp. 53-61.

McGowan, S., Oellig, C., Birru, W.A., Caradoc-Davies, T.T., Stack, C.M., Lowther, J., Skinner-Adams, T.S., Mucha, A., Kafarski, P., Grembecka, J., Trenholme, K.R., Buckle, A.M., Gardiner, D.L., Dalton, J.P., Whisstock, J., 2010, Structure of the Plasmodium falciparum M17 aminopeptidase and significance for the design of drugs targeting the neutral exopeptidases, Proceedings Of The National Academy Of Sciences Of The United States Of America [P], vol 107, issue 6, National Academy of Sciences, USA, pp. 2449-2454.

Kennan, R.M., Wong, W., Dhungyel, O., Han, X., Wong, D.M., Parker, D., Rosado, C.J., Law, R.H., McGowan, S., Reeve, S.B., Levina, V., Powers, G.A., Pike, R.N., Bottomley, S.P., Smith, A.I., Marsh, I., Whittington, R.J., Whisstock, J., Porter, C.J., Rood, J.I., 2010, The subtilisin-like protease AprV2 is required for virulence and uses a novel disulphide-tethered exosite to bind substrates, Plos Pathogens [P], vol 6, issue 11, Public Library of Science, USA, pp. 1-12.

Ong, P.C., Golding, S.J., Pearce, M.C., Irving, J.A., Grigoryev, S.A., Pike, D., Langendorf, C.G., Bashtannyk-Puhalovich, T.A., Bottomley, S.P., Whisstock, J.C., Pike, R.N., McGowan, S., 2009, Conformational change in the chromatin remodelling protein MENT, PL o S One, vol 4, issue 3 (e4727), Public Library of Science, USA, pp. 1-5.

Cheung, K.J., Awad, M.M., McGowan, S., Rood, J.I., 2009, Functional analysis of the VirSR phosphorelay from Clostridium perfringens, PLoS ONE [P], vol 4, issue 6 (e5849), Public Library of Science, USA, pp. 1-11.

McGowan, S., Porter, C.J., Lowther, J., Stack, C.M., Golding, S.J., Skinner-Adams, T.S., Trenholme, K.R., Teuscher, F., Donnelly, S.M., Grembecka, J., Mucha, A., Kafarski, P., DeGori, R., Buckle, A.M., Gardiner, D.L., Whisstock, J.C., Dalton, J.P., 2009, Structural basis for the inhibition of the essential Plasmodium falciparum M1 neutral aminopeptidase, Proceedings of the National Academy of Sciences of the United States of America, vol 106, issue 8, National Academy of Sciences, USA, pp. 2537-2542.

Fischer, K., Langendorf, C., Irving, J.A., Reynolds, S., Willis, C., Beckham, S.A., Law, R.H.P., Yang, S., Bashtannyk-Puhalovich, T.A., McGowan, S., Whisstock, J., Pike, R.N., Kemp, D.J., Buckle, A.M., 2009, Structural mechanisms of inactivation in scabies mite serine protease paralogues, Journal of Molecular Biology [P], vol 390, issue 4, Academic Press, UK, pp. 635-645.

Androulakis, S.G., Schmidberger, J., Bate, M.A., DeGori, R., Beitz, A., Keong, C., Cameron, B., McGowan, S., Porter, C.J., Harrison, A., Hunter, J., Martin, J.L., Kobe, B., Dobson, R.C., Parker, M.W., Whisstock, J., Gray, J., Treloar, A.E., Groenewegen, D., Dickson, N., Buckle, A.M., 2008, Federated repositories of X-ray diffraction images, Acta Crystallographica. Section D: Biological Crystallography, vol 64, issue 7, Wiley-Blackwell Munksgaard, Denmark, pp. 810-814.

Ong, P.C., McGowan, S., Pearce, M.C., Irving, J.A., Kan, W., Grigoryev, S.A., Turk, B., Silverman, G.A., Brix, K., Bottomley, S.P., Whisstock, J., Pike, R.N., 2007, DNA accelerates the inhibition of human cathepsin V by serpins, Journal of Biological Chemistry, vol 282, issue 51, American Society of Biochemistry & Molecular Biology Inc, Bethesda MD USA, pp. 36980-36986.

Porter, C.J., Schuch, R., Pelzek, A.J., Buckle, A.M., McGowan, S., Wilce, M.C.J., Rossjohn, J., Russell, R., Nelson, D., Fischetti, V.A., Whisstock, J.C., 2007, The 1.6 angstrom crystal structure of the catalytic domain of PlyB, a bacteriophage lysin active against Bacillus anthracis, Journal of Molecular Biology, vol 366, issue 2, Academic Press Ltd, Elsevier Science Ltd, London UK, pp. 540-550.

Law, R.H.P., Zhang, Q., McGowan, S., Buckle, A.M., Silverman, G.A., Wong, W., Rosado, C.J., Langendorf, C., Pike, R.N., Bird, P.I., Whisstock, J., 2006, An overview of the serpin superfamily, Genome Biology, vol 7, issue 5, Biomed Central Ltd, London UK, pp. 216-1-216-11.

McGowan, S., Buckle, A.M., Irving, J.A., Ong, P.C., Bashtannyk-Puhalovich, T.A., Kan, W., Henderson, K., Bulynko, Y.A., Popova, E.Y., Smith, A.I., Bottomley, S.P., Rossjohn, J., Grigoryev, S.A., Pike, R.N., Whisstock, J.C., 2006, X-ray crystal structure of MENT: evidence for functional loop-sheet polymers in chromatin condensation, The EMBO Journal, vol 25, issue 13, Nature Publishing Group, New York USA, pp. 3144-3155.

McGowan, S., O'Connor, J.R., Cheung, J.K., Rood, J.I., 2003, The SKHR motif is required for biological function of the VirR response regulator from Clostridium perfringens, Journal of Bacteriology, vol 185, issue 20, American Society for Microbiology, Washington USA, pp. 6205-6208.

McGowan, S., Lucet, I.S., Cheung, J.K., Awad, M.M., Whisstock, J.C., Rood, J.I., 2002, The FxRxHrS motif: a conserved region essential for DNA binding of the VirR response regulator from Clostridium perfringens, Journal of Molecular Biology, vol 322, issue 5, Academic Press Ltd Elsevier Science Ltd, London England, pp. 997-1011.