An Integrated Approach Towards Development of Highly Specific Chemotherapeutics. Many diseases are caused or can be treated by modifying the activities of particular enzymes. Molecules that affect enzymatic activities have potential as therapeutic agents. A successful approach to the discovery of new drug molecules is to design them based on very detailed knowledge of how the target enzyme works. In this project, a highly motivated team of scientists will use state of the art instruments and the ....An Integrated Approach Towards Development of Highly Specific Chemotherapeutics. Many diseases are caused or can be treated by modifying the activities of particular enzymes. Molecules that affect enzymatic activities have potential as therapeutic agents. A successful approach to the discovery of new drug molecules is to design them based on very detailed knowledge of how the target enzyme works. In this project, a highly motivated team of scientists will use state of the art instruments and their combined creativity to understand the intimate details of how one large group of enzymes work. The enzymes selected are the bimetallic hydrolases, many of which are associated with disorders including osteoporosis, mental illnesses, cystic fibrosis and various types of cancer.Read moreRead less
Guarding and evolving the genome: interactions between DNA-repair enzymes and damaged DNA. The application of structural biology techniques to the area of DNA repair allows us to understand the full implications linking genes and proteins to the molecular mechanisms of diseases such as cancer and hereditory conditions. Studies in this highly internationally competitive area are already established in the Bond laboratory, which has recently relocated to Australia. The use of forward-thinking stru ....Guarding and evolving the genome: interactions between DNA-repair enzymes and damaged DNA. The application of structural biology techniques to the area of DNA repair allows us to understand the full implications linking genes and proteins to the molecular mechanisms of diseases such as cancer and hereditory conditions. Studies in this highly internationally competitive area are already established in the Bond laboratory, which has recently relocated to Australia. The use of forward-thinking structural biology approaches to solve difficult technical problems will foster collaborations within Australia and with leading laboratories abroad, providing excellent up-to-date research training for students and postdoctoral researchers.
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Hierarchical Phosphorylation of Tyrosine Hydroxylase is Dependent on the Activation Sequence of Signaling Pathways. Protein phosphorylation is a fundamental process in biology. It controls protein expression and function in all cells. Hierarchical phosphorylation is defined as the phosphorylation of a protein at one site leading to an altered phosphorylation at another site on the same protein and an altered biological outcome. We have discovered that the enzyme tyrosine hydroxylase undergoes a ....Hierarchical Phosphorylation of Tyrosine Hydroxylase is Dependent on the Activation Sequence of Signaling Pathways. Protein phosphorylation is a fundamental process in biology. It controls protein expression and function in all cells. Hierarchical phosphorylation is defined as the phosphorylation of a protein at one site leading to an altered phosphorylation at another site on the same protein and an altered biological outcome. We have discovered that the enzyme tyrosine hydroxylase undergoes a form of hierarchical phosphorylation not previously reported. Here we examine hierarchical phosphorylation in rat and human tyrosine hydroxylase and its functional consequence in intact cells. The approaches and methods developed will also be applicable to investigation of hierarchical phosphorylation in other proteins.Read moreRead less
Function and regulation of the Na+,K+-ATPase. The Na+,K+-ATPase is the major energy-consuming enzyme of animal cells. Its ion pumping is essential for numerous physiological functions (e.g. heart, kidney, brain). Molecular detail of its pumping mechanism is, however, lacking and its regulation is still unclear. We will use rapid reaction methods on purified enzyme in vitro to locate the rate-determining step of the enzyme cycle, determine its mechanism, investigate its regulation by sodium conce ....Function and regulation of the Na+,K+-ATPase. The Na+,K+-ATPase is the major energy-consuming enzyme of animal cells. Its ion pumping is essential for numerous physiological functions (e.g. heart, kidney, brain). Molecular detail of its pumping mechanism is, however, lacking and its regulation is still unclear. We will use rapid reaction methods on purified enzyme in vitro to locate the rate-determining step of the enzyme cycle, determine its mechanism, investigate its regulation by sodium concentration, phosphorylation and membrane composition, and isolate its charge-transporting steps. The results will have immediate impact on the understanding of the enzyme's mechanism, its metabolic control and its role in disease.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
The control of elongation factor 2 and its role in the regulation of protein synthesis. Protein synthesis is a key process in living cells. The main stage, elongation, is regulated through phosphorylation of elongation factor eEF2 in response to hormones, amino acids and cellular energy status, via changes in the activity of eEF2 kinase. We will study how these conditions control eEF2 kinase by studying its phosphorylation and identifying new kinases that regulate it. We will explore the role of ....The control of elongation factor 2 and its role in the regulation of protein synthesis. Protein synthesis is a key process in living cells. The main stage, elongation, is regulated through phosphorylation of elongation factor eEF2 in response to hormones, amino acids and cellular energy status, via changes in the activity of eEF2 kinase. We will study how these conditions control eEF2 kinase by studying its phosphorylation and identifying new kinases that regulate it. We will explore the role of eEF2 in controlling protein synthesis, seek new substrates for eEF2 kinase and initiate work to elucidate the structure of this unusual enzyme. This will enhance, in a range of ways, fundamental understanding of cell physiology.Read moreRead less
Three-dimensional structures, substrate specificities and catalytic mechanisms of polysaccharide synthases. Plant wall polysaccharides are extensively used for food and fibre, and are important dietary components in human nutrition. A precise knowledge of mechanisms used by plants to synthesize these polysaccharides is unavailable, but would reveal potential routes to manipulate their biosynthesis in important crop species. For example, the levels or structures of polysaccharides might be modif ....Three-dimensional structures, substrate specificities and catalytic mechanisms of polysaccharide synthases. Plant wall polysaccharides are extensively used for food and fibre, and are important dietary components in human nutrition. A precise knowledge of mechanisms used by plants to synthesize these polysaccharides is unavailable, but would reveal potential routes to manipulate their biosynthesis in important crop species. For example, the levels or structures of polysaccharides might be modified to improve their efficacy as anti-cancer agents in human diets, to enhance digestibility of animal stock feeds, or to synthesise pharmologically valuable compounds. Thus, economic, social and environmental benefits will flow to both producers and consumers. Read moreRead less
Structure-based design of anti-osteoporotic drug leads: an integrated approach. One of the major consequences of Australia's aging population is that age-related diseases, such as osteoporosis, are increasing. Apart from the significant human suffering caused by this disease, there is an immense financial burden on the community, patients and their families. Current treatments for osteoporosis are often ineffective and also have major side-effects. An enzyme has been identified which plays a cru ....Structure-based design of anti-osteoporotic drug leads: an integrated approach. One of the major consequences of Australia's aging population is that age-related diseases, such as osteoporosis, are increasing. Apart from the significant human suffering caused by this disease, there is an immense financial burden on the community, patients and their families. Current treatments for osteoporosis are often ineffective and also have major side-effects. An enzyme has been identified which plays a crucial role in the progression of this disease by increasing the rate of bone-thinning. We will make compounds to slow down this enzyme. This project will provide the basis for the future development of new and improved drugs to treat osteoporosis.Read moreRead less
Regulation and function of a novel protein tyrosine phosphatase. A cell's ability to respond to its extracellular environment involves a complex and highly organised series of events referred to as cellular signalling. These signalling processes regulate fundamental cellular processes that underlie the growth and development of all living organisms. This proposal focuses on a group of enzymes known as the protein tyrosine phosphatases and their ability to regulate tyrosine phosphorylation-depe ....Regulation and function of a novel protein tyrosine phosphatase. A cell's ability to respond to its extracellular environment involves a complex and highly organised series of events referred to as cellular signalling. These signalling processes regulate fundamental cellular processes that underlie the growth and development of all living organisms. This proposal focuses on a group of enzymes known as the protein tyrosine phosphatases and their ability to regulate tyrosine phosphorylation-dependent signalling. We have identified a novel human protein tyrosine phosphatase and we aim to characterise its regulation and biological function.Read moreRead less
Characterisation of a novel protein tyrosine phosphatase. A cells ability to respond to its extracellular environment involves a complex and highly organised series of events referred to as cellular signalling. These signalling processes regulate fundamental cellular events that underlie the growth and development of all living organisms. This proposal focuses on a group of enzymes known as the protein tyrosine phosphatases and their ability to regulate tyrosine phosphorylation-dependent signa ....Characterisation of a novel protein tyrosine phosphatase. A cells ability to respond to its extracellular environment involves a complex and highly organised series of events referred to as cellular signalling. These signalling processes regulate fundamental cellular events that underlie the growth and development of all living organisms. This proposal focuses on a group of enzymes known as the protein tyrosine phosphatases and their ability to regulate tyrosine phosphorylation-dependent signalling. We have identified a novel human protein tyrosine phosphatase and we aim to characterise its function and the mechanism by which it is regulated.Read moreRead less