Structural studies of mammalian dimeric dihydrodiol dehydrogenase and L-xylulose reductase. The aim of the research is determine the structures and mechanisms of mammalian dimeric dihrodiol dehydrogenase and L-xylulose reductase. Mammalian dihydrodiol dehydrogenase exists in multiple forms in mammalian tissues. The dimeric form of the enzyme has a primary structure distinct from previously known mammalian enzymes and may constitute a novel protein family with prokaryotic proteins. L-Xylulose ....Structural studies of mammalian dimeric dihydrodiol dehydrogenase and L-xylulose reductase. The aim of the research is determine the structures and mechanisms of mammalian dimeric dihrodiol dehydrogenase and L-xylulose reductase. Mammalian dihydrodiol dehydrogenase exists in multiple forms in mammalian tissues. The dimeric form of the enzyme has a primary structure distinct from previously known mammalian enzymes and may constitute a novel protein family with prokaryotic proteins. L-Xylulose reductase is an enzyme of the uronate cycle that accounts for about 5% of the total glucose metabolism per day in humans. We propose to determine the first structure of a L-xylulose reductase.Read moreRead less
Studies on the stereospecific interaction between aldose reductase and inhibitor. There is no therapy specific for treatment of diabetes complications accepted worldwide. The enzyme aldose reductase has shown promising results as a drug target for preventing or delaying the onset of the complications. The structures of human aldose reductase holoenzyme in complex with stereoisomers of the potent inhibitor Fidarestat will be determined at high resolution in order to elucidate the binding modes re ....Studies on the stereospecific interaction between aldose reductase and inhibitor. There is no therapy specific for treatment of diabetes complications accepted worldwide. The enzyme aldose reductase has shown promising results as a drug target for preventing or delaying the onset of the complications. The structures of human aldose reductase holoenzyme in complex with stereoisomers of the potent inhibitor Fidarestat will be determined at high resolution in order to elucidate the binding modes responsible for the differences in their inhibitory potencies. The results may lead to the design of better inhibitors of the enzyme for the treatment of diabetes sufferers, at least until better methods for maintaining metabolic control are developed.Read moreRead less
Structure-based discovery of dipeptidyl peptidase IV inhibitors. Diabetes afflicts approximately 151 million people worldwide, with an estimated increase to 221 million by 2010. To date, no therapy for the treatment of diabetes complications is widely accepted. The enzyme dipeptidyl peptidase IV has shown promising results as a target for the treatment of type 2 diabetes. Structural studies of dipeptidyl peptidase IV in complex with inhibitor will be conducted to elucidate the details of the e ....Structure-based discovery of dipeptidyl peptidase IV inhibitors. Diabetes afflicts approximately 151 million people worldwide, with an estimated increase to 221 million by 2010. To date, no therapy for the treatment of diabetes complications is widely accepted. The enzyme dipeptidyl peptidase IV has shown promising results as a target for the treatment of type 2 diabetes. Structural studies of dipeptidyl peptidase IV in complex with inhibitor will be conducted to elucidate the details of the enzyme-inhibitor interaction. The results will be used to identify the molecular basis of potency and selectivity of dipeptidyl peptidase IV inhibitors and may lead to the discovery of pharmaceutical agents for the treatment of diabetes sufferers.Read moreRead less
Crystallographic studies of aldose and aldehyde reductases. The ability of aldose reductase to reduce the excess glucose that results from the hyperglycaemia of diabetes has been linked to the development of diabetic complications. Recent studies link the lack of a clinically suitable aldose reductase inhibitor to lack of inhibitor selectivity. The structures of the complexes of aldose and aldehyde reductases with various inhibitors should allow us to establish the important aspects of the inh ....Crystallographic studies of aldose and aldehyde reductases. The ability of aldose reductase to reduce the excess glucose that results from the hyperglycaemia of diabetes has been linked to the development of diabetic complications. Recent studies link the lack of a clinically suitable aldose reductase inhibitor to lack of inhibitor selectivity. The structures of the complexes of aldose and aldehyde reductases with various inhibitors should allow us to establish the important aspects of the inhibitor interaction with the residues of the active site. This information will be used in the design of more specific aldose reductase inhibitors.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0668017
Funder
Australian Research Council
Funding Amount
$1,047,000.00
Summary
Membrane Protein Structure and Interaction Facility. While it is estimated that a third of the human genome encodes for membrane proteins, the structures of only relatively few membrane proteins are currently known. It will be some time before membrane protein structure determination becomes routine, yet over 50% of the drugs on the market today rely on the activity of membrane proteins for their efficacy. This application seeks to establish a Membrane Protein Structure and Interaction Facility ....Membrane Protein Structure and Interaction Facility. While it is estimated that a third of the human genome encodes for membrane proteins, the structures of only relatively few membrane proteins are currently known. It will be some time before membrane protein structure determination becomes routine, yet over 50% of the drugs on the market today rely on the activity of membrane proteins for their efficacy. This application seeks to establish a Membrane Protein Structure and Interaction Facility for the development and application of novel techniques and approaches to study the structure and interactions of membrane proteins. Research progress will be greatly enhanced by the establishment of this dedicated facility with cutting-edge technologies for the study of membrane proteins.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0989504
Funder
Australian Research Council
Funding Amount
$1,400,000.00
Summary
Melbourne Biomolecular NMR Network. The Melbourne Biomolecular Nuclear Magnetic Resonance (NMR) Network will support a broad range of basic research activities with long-term benefits for diagnosis, treatment and prevention of numerous diseases. Metabolomics studies will identify human disease markers and characterise the physiological consequences of pharmaceutical intervention. Reverse chemical genetics approaches will identify new drug candidates and reveal novel mechanisms for regulating t ....Melbourne Biomolecular NMR Network. The Melbourne Biomolecular Nuclear Magnetic Resonance (NMR) Network will support a broad range of basic research activities with long-term benefits for diagnosis, treatment and prevention of numerous diseases. Metabolomics studies will identify human disease markers and characterise the physiological consequences of pharmaceutical intervention. Reverse chemical genetics approaches will identify new drug candidates and reveal novel mechanisms for regulating the activities of target proteins. Structural and dynamics studies will reveal molecular details of drug/candidate action and provide guidance for rational improvements. Overall, the planned research activities will have significant benefits for human health.Read moreRead less
The role of gamma glutamyl cyclotransferase in glutathione homeostasis. The aim of this study is to understand the structure and function of gamma-glutamyl cyclotransferase (GGCT) and its role in glutathione synthesis and turnover. Glutathione is essential for life and serves multiple biological functions protecting against oxidative stress, and aiding in the detoxification and excretion of foreign chemicals. This study will explore a new approach to changing intracellular glutathione concentra ....The role of gamma glutamyl cyclotransferase in glutathione homeostasis. The aim of this study is to understand the structure and function of gamma-glutamyl cyclotransferase (GGCT) and its role in glutathione synthesis and turnover. Glutathione is essential for life and serves multiple biological functions protecting against oxidative stress, and aiding in the detoxification and excretion of foreign chemicals. This study will explore a new approach to changing intracellular glutathione concentrations that has wide applications in the treatment of inherited enzyme deficiencies, cancer and the development of herbicide resistant crop plants. The study will also contribute to the training of scientists for the future development of the Australian biotechnology industryRead moreRead less
Cross-linked Tyrosine Residues in Peptides and Proteins. Many peptides and proteins have recently been found to contain unusual structural modifications, commonly in the form of cross-linked tyrosine residues. The aims of this project are to design and synthesise examples of these cross-linked tyrosine structures, thereby enabling the preparation of models of the modified proteins. Outcomes of this research will include an increased understanding of the relationship between the three-dimensional ....Cross-linked Tyrosine Residues in Peptides and Proteins. Many peptides and proteins have recently been found to contain unusual structural modifications, commonly in the form of cross-linked tyrosine residues. The aims of this project are to design and synthesise examples of these cross-linked tyrosine structures, thereby enabling the preparation of models of the modified proteins. Outcomes of this research will include an increased understanding of the relationship between the three-dimensional structure and biological activity of peptides/proteins, the generation of lead compounds for new anti-bacterial and anti-fungal pharmaceuticals, and the preparation of biological 'markers' of the processes involved in neurodegenerative diseases and aging.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0453832
Funder
Australian Research Council
Funding Amount
$550,910.00
Summary
New directions in biomolecular mass spectrometry. The combined UoW/ANU mass spectrometry facility supports a range of research projects in high priority areas including proteomics, mechanisms of aging, anticancer drugs and pathogenicity. The facility has several key deficiencies: 1) the ability to study very high molecular weight biomolecular complexes, 2) the ability to study ion-molecule interactions that have implications in mechanisms of chemistry in nature, and 3) researchers at ANU lack es ....New directions in biomolecular mass spectrometry. The combined UoW/ANU mass spectrometry facility supports a range of research projects in high priority areas including proteomics, mechanisms of aging, anticancer drugs and pathogenicity. The facility has several key deficiencies: 1) the ability to study very high molecular weight biomolecular complexes, 2) the ability to study ion-molecule interactions that have implications in mechanisms of chemistry in nature, and 3) researchers at ANU lack essential walk-up access to high sensitivity protein sequence analysis (MS/MS). The placement of resources that address these deficiencies in one geographical region and collaboration between these institutions will produce a research interaction unique in Australia.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0989374
Funder
Australian Research Council
Funding Amount
$550,000.00
Summary
South Australian High-Resolution and Ion-Mobility Mass Spectrometry Facility. The analytical facility will enhance (i) fundamental research to understand the mechanisms of the reactions of charged species with neutral molecules, and (ii) the provision of structural information, including the precise atomic composition of any molecule, small or large. Research supported by this facility includes (a)nanotechnology, including supramolecular chemistry, (b) bioscience: cancer research, neurodegenera ....South Australian High-Resolution and Ion-Mobility Mass Spectrometry Facility. The analytical facility will enhance (i) fundamental research to understand the mechanisms of the reactions of charged species with neutral molecules, and (ii) the provision of structural information, including the precise atomic composition of any molecule, small or large. Research supported by this facility includes (a)nanotechnology, including supramolecular chemistry, (b) bioscience: cancer research, neurodegenerate diseases (e.g. Parkinson's disease) osteoarthritis, inflammation, cardiac diseases and synthetic approaches to anticancer and other drugs.Read moreRead less