Parker Laboratory: Structural biology and computational drug design
Proteins are one of the body's most essential building blocks and are the molecular engines that control all functions of the body. X-ray crystallography offers the means to view the three-dimensional structure of proteins at the atomic level. Since the majority of drugs interact with proteins, crystal structures have proved to be invaluable for the discovery and development of new drugs.
The work of our laboratory is internationally recognised with the determination of more than one hundred crystal structures including those of membrane-associating proteins, detoxifying enzymes and protein kinases. This work has provided insights into a number of diseases such as cancer, bacterial and viral infections, and neurological diseases such as Alzheimer's disease. In recent years we have been emphasising the translational aspects of our work with an increasing focus on structure-based drug discovery. This focus has been underpinned by the development of virtual screening and fragment screening platforms in-house, by funding from the Australian Cancer Research Foundation, and partnerships with a number of Biotechnology companies including CSL Limited and Janssen.
Keywords: Protein structure, X-ray crystallography, Structure-based drug design, Cancer, Alzheimer’s Disease, Parkinson’s Disease, Bacterial toxins
Dr Sophie Broughton, Post-doctoral Fellow
Dr Brett Bennetts, Post-doctoral Fellow
Gabriella Crespi, Research Assistant
Dr Urmi Dhagat, Post-doctoral Fellow
Larissa Doughty, Facility Manager
Dr Michael Gorman, Post-doctoral Fellow
Dr Stefan Hermans, Post-doctoral Fellow
Dr Belinda Michell, Laboratory Manager
Dr Luke Miles, Post-doctoral Fellow
Dr Craig Morton, Post-doctoral Fellow
Nancy Hancock, Research Assistant
Dr Jessica Holien, Post-doctoral Fellow
Dr Tracy Nero, Post-doctoral Fellow
Karen Steffi Cheung Tung Shing, PhD Student
Jasmina Markulic, PhD Student
Dr Michelle Christie, Post-doctoral Fellow
Brendan Stevenson, Honours Student
Bronte Johnstone, Honours Student
Click here for the results of a Google Scholar analysis of Michael's publications.
- Parker MW, Pattus F, Tucker AD, Tsernoglou D. Structure of the membrane-pore-forming fragment of colicin A. Nature 1989; 337: 93-96.
- Parker MW, Buckley JT, Postma JP, Tucker AD, Leonard K, Pattus F, Tsernoglou D. Structure of the Aeromonas toxin proaerolysin in its water-soluble and membrane-channel states. Nature 1994; 367: 292-295.
- Hu SH, Parker MW, Lei JY, Wilce MC, Benian GM, Kemp BE. Insights into autoregulation from the crystal structure of twitchin kinase. Nature 1994; 369: 581-584.
- Heierhorst J, Kobe B, Feil SC, Parker MW, Benian GM, Weiss KR, Kemp BE. Ca2+/S100 regulation of giant protein kinases. Nature 1996; 380: 636-639.
- Rossjohn J, Feil SC, McKinstry WJ, Tweten RK, Parker MW. Structure of a cholesterol-binding, thiol-activated cytolysin and a model of its membrane form. Cell 1997; 89: 685-692.
- Shatursky O, Heuck AP, Shepard LA, Rossjohn J, Parker MW, Johnson AE, Tweten RK. The mechanism of membrane insertion for a cholesterol-dependent cytolysin: a novel paradigm for pore-forming toxins. Cell 1999; 99: 293-299.
- Gilbert RJ, Jiménez JL, Chen S, Tickle IJ, Rossjohn J, Parker M, Andrew PW, Saibil HR. Two structural transitions in membrane pore formation by pneumolysin, the pore-forming toxin of Streptococcus pneumoniae. Cell 1999; 97; 647-655.
- Brown RJ, Adams JJ, Pelekanos RA, Wan Y, McKinstry WJ, Palethorpe K, Seeber RM, Monks TA, Eidne KA, Parker MW, Waters MJ. Model for growth hormone receptor activation based on subunit rotation within a receptor dimer. Nature Struct Mol Biol 2005; 12: 814-821.
- Hansen G, Hercus TR, McClure BJ, Stomski FC, Dottore M, Powell J, Ramshaw H, Woodcock JM, Xu Y, Guthridge M, McKinstry WJ, Lopez AF, Parker MW. The structure of the GM-CSF receptor complex reveals a distinct mode of cytokine receptor activation. Cell 2008; 134: 496-507.
- Miles LA, Crespi GAN, Doughty L, Parker MW. Bapineuzumab captures the N-terminus of the Alzheimer’s disease amyloid-beta peptide in a helical conformation. Sci Rep 2013; 3: 1302; DOI:10.1038/srep01302.
- Bennetts B, Parker MW. Molecular determinants of common gating of a CIC chloride channel. Nature Commun 2013; 4: 3507.
- Brooks AJ, Dai W, O’Mara ML, Abankwa D, Chabra Y, Pelekanos RA, Gardon O, Tunny KA, Blucher KM, Morton CJ, Parker MW, Sierecki E, Gambin Y, Alexandrov K, Wilson IA, Doxastakis M, Mark AE, Waters MJ. A new cytokine receptor activation paradigm: activation of JAK2 by the Growth Hormone Receptor. A mechanism for activation of JAK2 by the growth hormone receptor. Science 2014; 344: 710, 1249783-1-1249783-12.
- Nero TN, Morton CJ, Holien JK, Wielens J, Parker MW. Oncogenic protein interfaces: small molecules, big challenges. Nature Revs Cancer 2014; 14: 248-262.
- Ascher DB, Wielens J, Nero TL, Morton CJ, Parker MW. Potent hepatitis inhibitors bind directly to NS5A and reduce its affinity for RNA. Sci Reps 2014; 4: 4765.
- Watt AD, Crespi GAN, Down RA, Ascher DB, Gunn A, Perez KA, McLean CA, Villemagne VL, Parker MW, Barnham KJ, Miles LA. Do current therapeutic anti-Abeta antibodies for Alzheimer’s disease engage the target? Acta Neuropathol 2014, 127: 803-810.
- Broughton SE, Hercus TR, Hardy MP, McClure BJ, Nero TL, Dottore M, Huynh H, Braley H, Barry EF, Kan WL, Dhagat U, Scotney P, Hartman D, Busfield SJ, Owczarek CM, Nash AD, Wilson NJ, Parker MW, Lopez AF. Dual mechanism of IL-3 receptor blockade by an anti-cancer antibody. Cell Rep 2014, 8: 410-419.
- Crespi GAN, Hermans SJ, Parker MW, Miles LA. Molecular basis for mid-region amyloid-b capture by leading Alzheimer’s disease immunotherapies. Sci Reps 2015; 5: 9649.
- Lawrence SL, Feil SC, Morton CJ, Farrand AJ, Mulhern TD, Gorman MA, Wade KR, Tweten RK, Parker MW. Crystal structure of Streptococcus pneumoniae pneumolysin provides key insights into early steps of pore formation. Sci Reps 2015; 5: 14352.
- Crespi GAN, Hermans SJ, Parker MW, Miles LA. Molecular basis for mid-region amyloid-beta capture by leading Alzheimer’s disease immunotherapies. Sci Reps 2015; 5: 9649.
- Broughton SE, Hercus TR, Nero TL, Dottore M, McClure BJ, Dhagat U, Taing H, Gorman MA, King-Scott J, Lopez AF, Parker MW. Conformational changes in the GM-CSF receptor suggest a molecular mechanism for affinity conversion and receptor signalling. Structure 2016; 24: 1271-1281.
- Lawrence SL, Gorman MA, Feil SC, Mulhern TD, Kuiper MJ, Ratner AJ, Tweten RK, Morton CJ, Parker MW. Structural basis for receptor recognition by the human CD59-responsive cholesterol-dependent cytolysins. Structure 2016; 24: 1488-1498.
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