New Methods for Structural Biology in Solution. This project aims to expand the range of applications of nuclear magnetic resonance (NMR) spectroscopy in pharmaceutical research, where NMR spectroscopy is already used routinely for the identification of chemical compounds that bind to protein targets. The techniques developed aim at providing rapid and broadly applicable tools for 3D structure determinations of chemical compounds bound to their protein target, identification of protein-protein i ....New Methods for Structural Biology in Solution. This project aims to expand the range of applications of nuclear magnetic resonance (NMR) spectroscopy in pharmaceutical research, where NMR spectroscopy is already used routinely for the identification of chemical compounds that bind to protein targets. The techniques developed aim at providing rapid and broadly applicable tools for 3D structure determinations of chemical compounds bound to their protein target, identification of protein-protein interaction sites and characterization of protein motions. The limits of NMR spectroscopy will be pushed to analyse systems of significantly increased molecular weights. The project includes applications to drug targets such as the dengue virus NS2B/NS3 protease.Read moreRead less
New Methods for Structural Biology in Solution. New technologies will be developed that are sufficiently rapid and inexpensive to compete with and replace the mutagenesis experiments that biologists usually perform to identify and characterize the functionally important parts of a protein. Nuclear magnetic resonance (NMR) spectroscopy techniques in combination with various selective labelling schemes will be developed with the goal of identification and structural characterization of protein-lig ....New Methods for Structural Biology in Solution. New technologies will be developed that are sufficiently rapid and inexpensive to compete with and replace the mutagenesis experiments that biologists usually perform to identify and characterize the functionally important parts of a protein. Nuclear magnetic resonance (NMR) spectroscopy techniques in combination with various selective labelling schemes will be developed with the goal of identification and structural characterization of protein-ligand interactions at increased rates and enhanced accuracy. In addition, the three-dimensional structures of proteins and protein domains of biologically important functions and unknown fold will be determined by NMR. The project aims at techniques of direct impact in pharmaceutical industry.Read moreRead less
Fluorine-labelled proteins for NMR spectroscopy. The technique developed in this project has direct impact on pharmaceutical research: NMR spectroscopy is used routinely to identify chemical compounds that bind to protein targets. This project includes the development of novel assignment techniques of 19F-labelled proteins, so that 19F-NMR can be used to detect specific binding interactions. One of the methods proposed here is designed to reveal structural information about the binding mode in s ....Fluorine-labelled proteins for NMR spectroscopy. The technique developed in this project has direct impact on pharmaceutical research: NMR spectroscopy is used routinely to identify chemical compounds that bind to protein targets. This project includes the development of novel assignment techniques of 19F-labelled proteins, so that 19F-NMR can be used to detect specific binding interactions. One of the methods proposed here is designed to reveal structural information about the binding mode in solution with atomic detail. This knowledge can significantly accelerate drug development. It is otherwise only available from crystal structures that can not always be determined.Read moreRead less
Novel approaches for structural and functional analysis of the protein complex COG, a tether that controls intra-Golgi trafficking. Production and engineering of proteins are key methodologies of the life sciences in general and biotechnology in particular. Our ability to produce and analyse protein-based components of the cell determines the expense and speed of discovery, as well as the creation of new vaccines, drugs, and diagnostic methods. The current project aims to develop new approaches ....Novel approaches for structural and functional analysis of the protein complex COG, a tether that controls intra-Golgi trafficking. Production and engineering of proteins are key methodologies of the life sciences in general and biotechnology in particular. Our ability to produce and analyse protein-based components of the cell determines the expense and speed of discovery, as well as the creation of new vaccines, drugs, and diagnostic methods. The current project aims to develop new approaches for protein production and to apply them to the analysis of the basic mechanisms of cell self-maintenance.Read moreRead less
The molecular mechanism of retromer and sorting nexin function in endosomal membrane trafficking. The proposed research represents breakthrough science that will lead to a fundamental understanding at the molecular level of the structure and assembly of the retromer complex and how it regulates sorting of receptors in the endosomal system. It will provide excellent research training for top graduate students and post-doctoral scientists in multidisciplinary methods that constitute state-of the- ....The molecular mechanism of retromer and sorting nexin function in endosomal membrane trafficking. The proposed research represents breakthrough science that will lead to a fundamental understanding at the molecular level of the structure and assembly of the retromer complex and how it regulates sorting of receptors in the endosomal system. It will provide excellent research training for top graduate students and post-doctoral scientists in multidisciplinary methods that constitute state-of the-art structural and molecular cell biology research. By addressing an area of great interest internationally the project will have the capacity to increase Australia's knowledge base and strengthen it's reputation for research excellence.Read moreRead less
Endosomal Protein Transport: From Molecular Structures to Biological Function. Intracellular transport of biomolecules through the endosomal organelle is critical for normal cellular processes such as signalling, homoeostasis and development. Defects in this fundamental process and subversion of it by bacterial and viral pathogens also lead to many different human diseases. This project will build on Australia's strong programme of structural and cellular biology research to develop key insights ....Endosomal Protein Transport: From Molecular Structures to Biological Function. Intracellular transport of biomolecules through the endosomal organelle is critical for normal cellular processes such as signalling, homoeostasis and development. Defects in this fundamental process and subversion of it by bacterial and viral pathogens also lead to many different human diseases. This project will build on Australia's strong programme of structural and cellular biology research to develop key insights into endosomal trafficking at the molecular level. Outcomes from this work will place Australia at the forefront of international efforts to understand this essential biological process and will have important implications for future design of pharmaceuticals.Read moreRead less
Protein degradation in mammals. One mechanism by which the regulation of protein turnover occurs is the balance between the activity of enzymes responsible for the ubiquitination and deubiquitination of target proteins. The majority of targets of this second family of enzymes are unknown. This project proposes a method for the identification of the targets of two specific mammalian deubiquitinating enzymes in order to understand their function and to begin to explore this new research field. ....Protein degradation in mammals. One mechanism by which the regulation of protein turnover occurs is the balance between the activity of enzymes responsible for the ubiquitination and deubiquitination of target proteins. The majority of targets of this second family of enzymes are unknown. This project proposes a method for the identification of the targets of two specific mammalian deubiquitinating enzymes in order to understand their function and to begin to explore this new research field. Knowledge about this new aspect of protein degradation could provide a powerful tool to test the effect of the stabilisation or removal of specific proteins in the cell and also to develop new technologies in protein production.Read moreRead less
Enabling Technologies for Structural Genomics. New technologies will be developed to save time, money and effort in rapid preparation of protein samples for structural genomics. Systems will be devised for preparing sufficient isotope-labelled proteins for nuclear magnetic resonance spectroscopy without using living organisms, for efficiently identifying points at which proteins can be broken into smaller fragments with the right properties, and for joining the ends of proteins and peptides toge ....Enabling Technologies for Structural Genomics. New technologies will be developed to save time, money and effort in rapid preparation of protein samples for structural genomics. Systems will be devised for preparing sufficient isotope-labelled proteins for nuclear magnetic resonance spectroscopy without using living organisms, for efficiently identifying points at which proteins can be broken into smaller fragments with the right properties, and for joining the ends of proteins and peptides together to make them much more stable. This combination of technologies are widely applicable to current problems in protein chemistry, molecular biology, functional genomics and the medical sciences.Read moreRead less
Biomimetic Insights from Enamel: A Nano-mechanical and Nano-structural Investigation of a Natural Ceramic-like Biocomposite. Enamel is a naturally developed example of an optimised material structure that constitutes the hardest tissue in the human body. In addition it is exposed to severe mechanical and environmental challenges and must last the lifetime of the individual and unlike other tissue is unable to heal or repair itself. Understanding the factors controlling the amazing mechanical pr ....Biomimetic Insights from Enamel: A Nano-mechanical and Nano-structural Investigation of a Natural Ceramic-like Biocomposite. Enamel is a naturally developed example of an optimised material structure that constitutes the hardest tissue in the human body. In addition it is exposed to severe mechanical and environmental challenges and must last the lifetime of the individual and unlike other tissue is unable to heal or repair itself. Understanding the factors controlling the amazing mechanical properties of this tissue will be of great benefit for the design of bio-inspired materials and be important for the development of advanced materials for which Australia already has an enviable reputation.Read moreRead less
Heparan sulfate complexes with VEGF for control of angiogenesis in tissue engineered constructs. The national/community benefits that will arise from this work include, the generation of knowledge related to the growth of blood vessels in the presence of a synthetic polymer that has been made to look like the natural polymers present in the body. This will lead to an understanding of the underlying mechanisms involved that may have down stream effects relevant to the replacement of many types o ....Heparan sulfate complexes with VEGF for control of angiogenesis in tissue engineered constructs. The national/community benefits that will arise from this work include, the generation of knowledge related to the growth of blood vessels in the presence of a synthetic polymer that has been made to look like the natural polymers present in the body. This will lead to an understanding of the underlying mechanisms involved that may have down stream effects relevant to the replacement of many types of tissues being generated for clinical applications, including possible applications in the treatment of heart disease, the largest killer of people in the Western world. Read moreRead less