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.
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-electron microscopy (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.
Malaria parasite invasion
Our research also focuses on understanding the mechanisms by which malaria parasite invade human red blood cells. Malaria is an infectious disease of global significance causing close to 0.5 million deaths annually. We study the biology of blood stage infection because infection of red blood cells by malaria parasites is responsible for the clinical symptoms of malaria. Blood stage malaria antigens are important target for drug and vaccine development.
To invade red blood cells, the parasite utilises secretion machinery to display molecular “keys”, called invasion ligands that recognise specific receptors on the surface of red blood cells. These parasite ligand-host receptor interactions mediate signalling events in an orderly sequential manner to enable the parasite to move into red blood cells in a short space of 60 seconds. We aim to characterise these molecular ligand-receptor interactions by cryo-EM, as well as how these parasite ligands could be blocked by invasion inhibitory antibodies. This information will be fundamental for designing a potential malaria vaccine to mount effective immune responses to protect against malaria infection.
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.