Structural Biology of Inflammation and Cancer
Research Group Head
The Structural Biology of Inflammation and Cancer research group focuses on two complementary areas of research.
An important part of innate immunity is the ability of infected cells to sense and respond to infections by eliciting pro-inflammatory processes. Inflammasomes are key cytoplasmic sensors that detect pathogen components to undergo conversion from inactive to active signalling inflammasomes to drive inflammatory signalling. The activation status of inflammasomes is under tight-regulations to maintain healthy homeostasis, but mutations in inflammasome components can result in imbalance of inflammatory signalling which is the underlying basis of many autoinflammatory diseases. Our interest is focused on understanding how the activity of inflammasome is controlled and the mechanisms by which inflammasome sensors detect infections and the molecular details of inflammasome activation.
We use structural biology and cryo-EM to determine the structures of protein-nucleic acid complexes to understand inflammasome signalling at atomic resolution. Our goal is to advance knowledge in this area to enable development of therapeutics to treat diseases associated with malfunction of inflammasomes.
Genome maintenance in normal and cancer cells
The human genome is subjected to numerous genetic alterations throughout the lifespan of an individual as a consequence of exposure to environmental mutagens, such as UV-sun irradiation, cigarette smoke, as well as DNA damages induced by endogenous sources, eg, reactive oxygen species. These DNA damages are constantly monitored by genome surveillance mechanisms to ensure genome integrity is maintained. Malfunction of these surveillance and maintenance mechanisms predispose the genome to oncogenic changes, which ultimately led to the development of cancers. Furthermore, cancer cells have adapted specific genome maintenance mechanisms to ensure the appropriate genetic information are passed to the daughter cells during cell division, as well as the need to utilise DNA repair mechanisms in response to cancer chemotherapies. It is important to understand the molecular details on genome maintenance mechanisms to understand how normal cells maintain the heathy state, and how cancer cells develop.
Our research is focusing on protein-nucleic acid complexes that monitor and maintain the genome integrity of normal and cancer cells. Cells have sophisticated molecular machines that detect and repair these DNA alterations. We use cryo-EM and biochemical methods to characterise the mechanisms of these molecular machines to understand how genome integrity is maintained. The ultimate goal is to apply these knowledges to develop therapeutics that can offer new ways to treat disorders or cancers associated with genome instability.
Wong W*, Huang R*, Menant S, Hong C, Sandow JJ, Birkinshaw RW, Healer J, Hodder AN, Kanjee U, Tonkin CJ, Heckmann D, Soroka V, Sogaard TMM, Jorgensen T, Duraisingh MT, Czabotar PE, Jongh WAd, Tham WH, Webb AI, Yu Z, Cowman AF. (2019) Structure of Plasmodium falciparum Rh5-CyRPA-Ripr invasion complex, Nature. 565: 118-121. *co-first author
Wong W*, Bai XC*, Sleeb BE*, Triglia T*, Brown A, Thompson JK, Jackson KE, Hanssen E, Marapana DS, Fernandez IS, Ralph SA, Cowman AF, Scheres SHW, Baum J. (2017) Mefloquine targets the Plasmodium falciparum 80S ribosome to inhibit protein synthesis. Nature Microbiology 2 Article number: 17031. *co-first author
Wong W*, Bai XC*, Brown A*, Fernandez IS, Hanssen E, Condron M, Tan YH, Baum J, Scheres SH. (2014) Cryo-EM structure of the Plasmodium falciparum 80S ribosome bound to the anti-protozoan drug emetine eLife 3 – P12695994, *co-first author
Wong W, Skau CT, Marapana DS, Hanssen E, Taylor NL, Riglar DT, Zuccala ES, Angrisano F, Lewis H, Catimel B, Clarke OB, Kershaw NJ, Perugini MA, Kovar DR, Gulbis JM, Baum J. (2011) Minimal requirements for actin filament disassembly revealed by structural analysis of malaria parasite Actin Depolymerizing Factor 1, PNAS 108(24):9869-74.