Revealing molecular detail of DNA triplexes to underpin antigene technology. Variations from the classic DNA double helix structure are proposed to play key roles in a range of cellular processes, particularly gene regulation. However, the biological function and therapeutic potential of these unusual DNA structures are poorly explored, since the fundamental molecular details which govern their formation and interactions with cellular machinery are not well described. This project aims to develo ....Revealing molecular detail of DNA triplexes to underpin antigene technology. Variations from the classic DNA double helix structure are proposed to play key roles in a range of cellular processes, particularly gene regulation. However, the biological function and therapeutic potential of these unusual DNA structures are poorly explored, since the fundamental molecular details which govern their formation and interactions with cellular machinery are not well described. This project aims to develop innovative methods to investigate, and importantly modulate, DNA and RNA triple helix assembly, specificity and molecular interactions. Resulting insights will underpin novel approaches to gene regulation, principally in the context of designing new antibacterial agents to address the antibacterial resistance problem.Read moreRead less
Investigating pathways of lipoglycan formation in the bacterial cell wall. This project aims to investigate how the complex cell walls of Mycobacteria and Corynebacteria are assembled. The project will utilise a combination of genetic, biochemical and advanced analytical approaches to investigate individual steps in the synthesis of key cell wall components and understand how the assembly of these components is coordinated with bacterial growth. Important outcomes of this research will be detail ....Investigating pathways of lipoglycan formation in the bacterial cell wall. This project aims to investigate how the complex cell walls of Mycobacteria and Corynebacteria are assembled. The project will utilise a combination of genetic, biochemical and advanced analytical approaches to investigate individual steps in the synthesis of key cell wall components and understand how the assembly of these components is coordinated with bacterial growth. Important outcomes of this research will be detailed information on processes that regulate the growth of bacteria with important biotechnology, veterinary and medical significance, as well as information on mechanisms of cell wall synthesis that may be conserved in all bacteria.Read moreRead less
Undermining fungal defences by targeting their functional amyloid armour. This project will determine how a protective protein coating forms on the surface of fungal spores and infectious structures. This coating is comprised of amyloid protein fibrils and is used by fungi to improve efficiency of infection and to avoid detection by the host plant or animal. We have discovered novel small molecules that prevent the fibrils from forming. This project will use these molecules to reveal the details ....Undermining fungal defences by targeting their functional amyloid armour. This project will determine how a protective protein coating forms on the surface of fungal spores and infectious structures. This coating is comprised of amyloid protein fibrils and is used by fungi to improve efficiency of infection and to avoid detection by the host plant or animal. We have discovered novel small molecules that prevent the fibrils from forming. This project will use these molecules to reveal the details of the fibril assembly mechanism and find the best way to undermine this fungal defence system. This knowledge will enable the development of potent small molecule inhibitors to treat fungal infections that blight crops and harm animals, and the production of new layered biomaterials for nanotechnology applications.Read moreRead less
Biosynthetic LEGO: enzymatic redesign to produce new vancomycin analogues. This project aims to uncover the reengineering potential of the biosynthetic machinery that produces glycopeptide antibiotics by advancing our understanding of how the core peptide production line functions. Natural product biosynthesis often produces complex peptide structures, with one important example being the glycopeptide antibiotics. This project expects to generate new knowledge about enzymatic peptide biosynthesi ....Biosynthetic LEGO: enzymatic redesign to produce new vancomycin analogues. This project aims to uncover the reengineering potential of the biosynthetic machinery that produces glycopeptide antibiotics by advancing our understanding of how the core peptide production line functions. Natural product biosynthesis often produces complex peptide structures, with one important example being the glycopeptide antibiotics. This project expects to generate new knowledge about enzymatic peptide biosynthesis using a highly interdisciplinary approach and previously developed tools. The anticipated outcomes of this project will be an enhanced understanding of how such complex peptide biosynthesis is performed, which is knowledge vital for future efforts to reengineer such biosynthetic peptide assembly lines as a series of modular LEGO blocks to produce new bioactive peptides.Read moreRead less
The RGG/RG motif as an RNA chaperone: advancing CRISPR-Cas RNA technology. This project investigates the way in which protein molecules interact effectively with RNA molecules and also aims to enhance the CRISPR-Cas13a system for RNA detection. Innovative approaches will be used to test the role of a particular protein motif, called the RGG/RG motif, in remodelling RNA structure and enhancing the Cas13a protein. This knowledge is expected to shift our understanding of protein-RNA interactions th ....The RGG/RG motif as an RNA chaperone: advancing CRISPR-Cas RNA technology. This project investigates the way in which protein molecules interact effectively with RNA molecules and also aims to enhance the CRISPR-Cas13a system for RNA detection. Innovative approaches will be used to test the role of a particular protein motif, called the RGG/RG motif, in remodelling RNA structure and enhancing the Cas13a protein. This knowledge is expected to shift our understanding of protein-RNA interactions that are fundamental to almost every aspect of cell biology. The project is intended to benefit Australia through contributing to fundamental knowledge in the field, facilitating the development of new CRISPR-Cas biotechnologies for RNA detection and through the training of young researchers in frontier technologies. Read moreRead less
Integrating quantum hyperpolarisation in nuclear magnetic resonance systems. This project aims to integrate quantum hyperpolarisation technology into state-of-the-art nuclear magnetic resonance (NMR) systems, potentially boosting the signal by several orders of magnitude. Understanding the structure and function of membrane bound peptides and proteins in cells in their native environments is critical in drug development. However, studying these biomolecules by conventional NMR under ambient cond ....Integrating quantum hyperpolarisation in nuclear magnetic resonance systems. This project aims to integrate quantum hyperpolarisation technology into state-of-the-art nuclear magnetic resonance (NMR) systems, potentially boosting the signal by several orders of magnitude. Understanding the structure and function of membrane bound peptides and proteins in cells in their native environments is critical in drug development. However, studying these biomolecules by conventional NMR under ambient conditions is challenging due to sensitivity limitations. The technology developed by this project will be a significant step forward in NMR and the new science enabled may have far reaching consequences for the study of peptides and proteins of live cells for the development of new drugs and anti-biotics, with direct societal benefits and flow-on economic benefits.Read moreRead less
Novel conotoxins that target ion channels and receptors. This project will discover peptides from cone snail venom that are potential drug candidates. The project will expand our knowledge of these biological active peptides and their mode of action. It will also protect key molecules through patent applications, providing a competitive edge for Australian biotechnology.
Mass spectrometry to reveal the role of lipids in protein misfolding. This project aims to develop an integrated mass spectrometry-based approach to determine structures and dynamics of membrane associated proteins, and discover how lipids cause protein misfolding implicated in neurodegeneration. Lipid membranes may influence protein (mis)folding, aggregation and related toxicity. However, the complex and dynamic nature of the lipid-protein interactions involved means traditional methods cannot ....Mass spectrometry to reveal the role of lipids in protein misfolding. This project aims to develop an integrated mass spectrometry-based approach to determine structures and dynamics of membrane associated proteins, and discover how lipids cause protein misfolding implicated in neurodegeneration. Lipid membranes may influence protein (mis)folding, aggregation and related toxicity. However, the complex and dynamic nature of the lipid-protein interactions involved means traditional methods cannot easily characterise them, and they are poorly understood at a molecular level. The project expects to develop tools to bridge a critical gap in structural biology, while understanding lipid-protein interactions could lead to new therapies. This will ultimately provide benefits such as reduced health costs and better health outcomes.Read moreRead less
Molecular study of copper-promoted ubiquitination. This project aims to study copper-promoted ubiquitination, a novel discovery that a conserved copper binding site in conjugating enzyme UBE2D2 promotes ubiquitination of a range of proteins including tumor suppressor p53. It predicts a correlation between copper homeostasis and cellular proteostasis and may rationalise an inverse relationship between Alzheimer's disease and cancer. This project will employ a range of integrated approaches to ill ....Molecular study of copper-promoted ubiquitination. This project aims to study copper-promoted ubiquitination, a novel discovery that a conserved copper binding site in conjugating enzyme UBE2D2 promotes ubiquitination of a range of proteins including tumor suppressor p53. It predicts a correlation between copper homeostasis and cellular proteostasis and may rationalise an inverse relationship between Alzheimer's disease and cancer. This project will employ a range of integrated approaches to illuminate the molecular nature of this copper action. Expected outcomes include an understanding of the molecular mechanisms of this process, and enhanced interdisciplinary collaboration. Potential benefits include new strategies to intervene in copper-related disorders.Read moreRead less
Development of potent and specific modulators of the human sodium channel Nav1.7. There are few effective drugs available for the treatment of chronic pain. This team recently discovered that spider venoms are a rich source of inhibitors of Nav1.7, a new target for anti-pain drugs. The goal of this project is to develop potent blockers of Nav1.7 that can be used to critically assess the role of this ion channel in mediating pain.