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
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
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
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
Identification of functionally important autophosphorylation site(s) on ataxia telangiectasia and Rad 3 - related (ATR) protein kinase. The integrity of our genetic material must be maintained so that it can be passed on from one generation to the next and also to minimize the risk of cancer and other pathologies in an individual. There are multiple proteins involved in protecting our DNA including several enzymes that detect and signal DNA damage to a series of pathways involved in halting the ....Identification of functionally important autophosphorylation site(s) on ataxia telangiectasia and Rad 3 - related (ATR) protein kinase. The integrity of our genetic material must be maintained so that it can be passed on from one generation to the next and also to minimize the risk of cancer and other pathologies in an individual. There are multiple proteins involved in protecting our DNA including several enzymes that detect and signal DNA damage to a series of pathways involved in halting the passage of cells through the cell cycle so that repair can occur. This project studies the mechanism of action of one of these enzymes which will be of benefit in designing new compounds to fight disease. Read moreRead less
Understanding mechanistic and systemic regulation of protein prenyltransferases. The proposed research will expand our understanding of lipid-conjugating enzymes that are critical for a multitude of normal cellular functions. We seek to reveal the basic workings of cells and help to explain the development and complexity of signalling networks in eukaryotic evolution. The findings will enable us to explore and exploit the catalytic properties of these lipid-related enzymes for applications in bi ....Understanding mechanistic and systemic regulation of protein prenyltransferases. The proposed research will expand our understanding of lipid-conjugating enzymes that are critical for a multitude of normal cellular functions. We seek to reveal the basic workings of cells and help to explain the development and complexity of signalling networks in eukaryotic evolution. The findings will enable us to explore and exploit the catalytic properties of these lipid-related enzymes for applications in biotechnology. The ultimate aim is to create novel technologies for protein production, modification and analysis that will accelerate the pace of discovery in protein research, basic cell and organism biology, diagnostics, biotechnology and drug discovery. Read moreRead less
Structural studies on carbohydrate modifying enzymes. Carbohydrates form one of four major classes of biological macromolecules, and are major targets for drug design. We have developed methods for the production of carbohydrate synthesising enzymes and will determine the structures of these enzymes to provide the foundation for structure based design of inhibitors. The research will allow us to understand how these enzymes function in normal circumstances and how they malfunction in disease sta ....Structural studies on carbohydrate modifying enzymes. Carbohydrates form one of four major classes of biological macromolecules, and are major targets for drug design. We have developed methods for the production of carbohydrate synthesising enzymes and will determine the structures of these enzymes to provide the foundation for structure based design of inhibitors. The research will allow us to understand how these enzymes function in normal circumstances and how they malfunction in disease states such as cancer. The long-term outcome will be a significantly enhanced body of knowledge of this poorly understood group of enzymes and the development of new carbohydrate based chemicals with novel therapeutic applications.Read moreRead less