The main interest of our research is to understand the control of a cell death process called apoptosis, which is regulated by the Bcl-2 family of proteins, and to design therapeutics to target these proteins in disease.
In the past we have focused on how “guardian” proteins from the family keep the cell alive. Using information gleaned from our atomic characterization of these proteins we have worked with medicinal chemist colleagues to develop compounds to kill cancerous cells. Such drugs, so called BH3 mimetics, are now in the clinic for the treatment of chronic lymphocytic leukaemia (CLL) and acute myeloid leukaemia (AML), with the potential for other compounds to target family members in other cancer settings.
More recently we have switched our focus to the executioner members of the Bcl-2 family that are responsible for telling the cell to die. Our studies have revealed how executioners are activated and transformed into the entities that kill the cell. We now aim to use that information to develop drugs that can keep cells alive in setting such as stroke or neurodegenerative disorders in which tissue damage occurs to excessive cell death.
Understanding how the MLKL protein regulates necroptotic cell death.
We use structural biology, in particular protein crystallography and CryoEM supported by biochemical and biological analyses, to decipher these pathways. These tools allow us to observe the atomic details of cell death proteins, providing key insights into how they function at the molecular level and informing the development of therapeutic compounds capable of modulating their activity.
We also use these techniques to study other proteins important to human health, including:
Australia, Curtin University, BSc (Hons), PhD
The University of Melbourne
2019, Prime Minister’s Prize for Innovation (awarded with Prof David Huang, Prof Guillaume Lessene and Prof Andrew Roberts)
2018, Clunies Ross Knowledge Commercialisation Award (awarded with Prof David Huang, Prof Guillaume Lessene and Prof Andrew Roberts), Australian Academy of Technology and Engineering
2016 Johnson & Johnson Eureka Prize for Innovation in Medical Research (awarded with Prof David Huang, Prof Guillaume Lessene and Prof Andrew Roberts), The Australian Museum
2015 Gottschalk Medal, The Australian Academy of Science
2013 Burnet Prize, WEHI
2022 Investigator Grant, National Health and Medical Research Council
2021 Ideas Grant, National Health and Medical Research Council
2012, 2014, 2015, 2018 Project Grants (x4), National Health and Medical Research Council
2015 Senior Research Fellowship, National Health and Medical Research Council
2010 Future Fellowship, Australian Research Council
Meng Y, Davies KA, Fitzgibbon C, Young SN, Garnish SE, Horne CR, Luo C, Garnier JM, Liang LY, Cowan AD, Samson AL, Lessene G, Sandow JJ, ^Czabotar PE, ^Murphy JM. Human RIPK3 maintains MLKL in an inactive conformation prior to cell death by necroptosis. Nat Commun. 2021 Nov 22;12(1):6783 PMID: 34811356
Roy MJ, Vom A, Okamoto T, Smith BJ, Birkinshaw RW, Yang H, Abdo H, White CA, Segal D, Huang DCS, Baell JB, Colman PM, ^Czabotar PE, ^Lessene G. Structure- Guided Development of Potent Benzoylurea Inhibitors of BCL-XL and BCL-2. J Med Chem. 2021 May 13;64(9):5447-5469 PMID: 33904752
^Birkinshaw RW, Iyer S, Lio D, Luo CS, Brouwer JM, Miller MS, Robin AY, Uren RT, Dewson G, Kluck RM, Colman PM, ^Czabotar PE. Structure of detergent-activated BAK dimers derived from the inert monomer. Mol Cell. 2021 May 20;81(10):2123-2134 PMID: 33794146
Cowan AD, Smith NA, Sandow JJ, Kapp EA, Rustam YH, Murphy JM, Brouwer JM, Bernardini JP, Roy MJ, Wardak AZ, Tan IK, Webb AI, Gulbis JM, Smith BJ, Reid GE, Dewson G, ^Colman PM, ^Czabotar PE. BAK core dimers bind lipids and can be bridged by them. Nat Struct Mol Biol. 2020 Nov;27(11):1024-1031 PMID: 32929280
Davies KA, Fitzgibbon C, Young SN, Garnish SE, Yeung W, Coursier D, Birkinshaw RW, Sandow JJ, Lehmann WIL, Liang LY, Lucet IS, Chalmers JD, Patrick WM, Kannan N, Petrie EJ, ^Czabotar PE, ^Murphy JM. Distinct pseudokinase domain conformations underlie divergent activation mechanisms among vertebrate MLKL orthologues. Nat Commun. 2020 Jun 19;11(1):3060 PMID: 32561735
^Birkinshaw RW, Gong JN, Luo CS, Lio D, White CA, Anderson MA, Blombery P, Lessene G, Majewski IJ, Thijssen R, Roberts AW, Huang DCS, Colman PM, ^Czabotar PE. Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations. Nat Commun. 2019 Jun 3;10(1):2385. PMID: 31160589
Ke FFS, Vanyai HK, Cowan AD, Delbridge ARD, Whitehead L, Grabow S, Czabotar PE, Voss AK, Strasser A. Embryogenesis and Adult Life in the Absence of Intrinsic Apoptosis Effectors BAX, BAK, and BOK. Cell. 2018 May 17;173(5):1217-1230 PMID: 29775594
Brouwer JM, Lan P, Cowan AD, Bernardini JP, Birkinshaw RW, van Delft MF, Sleebs BE, Robin AY, Wardak A, Tan IK, Reljic B, Lee EF, Fairlie WD, Call MJ, Smith BJ, Dewson G, Lessene G, Colman PM, Czabotar PE. Conversion of Bim-BH3 from Activator to Inhibitor of Bak through Structure-Based Design. Mol Cell. 2017 Nov 16;68(4):659-72 e9. PMID: 29149594
Brouwer JD, Westphal D, Dewson G, Robin AY, Uren RT, Bartolo R, Thompson GV, Colman PM, Kluck RM, Czabotar PE. Bak core and latch domains separate during activation, and freed core domains form symmetric homodimers. Mol Cell. 2014 Sep 18;55(6):938-46. PMID: 25175025
*Hodder AN, *Sleebs BE, *Czabotar PE, Gazdik M, Xu Y, O’Neill MT, Lopaticki S, Nebl T, Triglia T, Smith BJ, Lowes K, Boddey JA, Cowman AF. Structural basis for plasmepsin V inhibition that blocks export of malaria proteins to human erythrocytes. Nat Struct Mol Biol. 2015 Aug;22(8):590-6. PMID: 26214367
*Czabotar PE, *Lessene G, Strasser A, Adams JM. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol. 2014 Jan;15(1):49-63. PMID: 24355989
Murphy JM, Lucet IS, Hildebrand JM, Tanzer MC, Young SN, Sharma P, Lessene G, Alexander WS, Babon JJ, Silke J, Czabotar PE. Insights into the evolution of divergent nucleotide-binding mechanisms among pseudokinases revealed by crystal structures of human and mouse MLKL. Biochem J. 2014 Feb 1;457(3):369-77. PMID: 24219132
*Czabotar PE, *Westphal D, Dewson G, Ma S, Hockings C, Fairlie WD, Lee EF, Yao S, Robin AY, Smith BJ, Huang DC, Kluck RM, Adams JM, Colman PM. Bax crystal structures reveal how BH3 domains activate Bax and nucleate its oligomerization to induce apoptosis. Cell. 2013 Jan 31;152(3):519-31. PMID: 23374347
Lessene G, Czabotar PE, Sleebs BE, Zobel K, Lowes KN, Adams JM, Baell JB, Colman PM, Deshayes K, Fairbrother WJ, Flygare JA, Gibbons P, Kersten WJ, Kulasegaram S, Moss RM, Parisot JP, Smith BJ, Street IP, Yang H, Huang DC, Watson KG. Structure-guided design of a selective BCL-X(L) inhibitor. Nat Chem Biol. 2013 Jun;9(6):390-7. PMID: 23603658
Okamoto T, Zobel K, Fedorova A, Quan C, Yang H, Fairbrother WJ, Huang DC, Smith BJ, Deshayes K, Czabotar PE. Stabilizing the pro-apoptotic BimBH3 helix (BimSAHB) does not necessarily enhance affinity or biological activity. ACS Chem Biol. 2013 Feb 15;8(2):297-302. PMID: 23151250
*Murphy JM, *Czabotar PE, *Hildebrand JM, Lucet IS, Zhang JG, Alvarez-Diaz S, Lewis R, Lalaoui N, Metcalf D, Webb AI, Young SN, Varghese LN, Tannahill GM, Hatchell EC, Majewski IJ, Okamoto T, Dobson RC, Hilton DJ, Babon JJ, Nicola NA, Strasser A, Silke J, Alexander WS. The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. Immunity. 2013 Sep 19;39(3):443-53. PMID: 24012422