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
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0561013
Funder
Australian Research Council
Funding Amount
$220,000.00
Summary
X-ray diffraction System for Protein Crystallography and Structural Biology. Knowledge of protein structures enables researchers to explain cellular function at a molecular level. In particular, it provides essential information to understand the mechanism of diseases, such as cancer or AIDS, and it ultimately leads to the design of better drugs.
An in-house X-ray protein crystallography facility will allow us to determine the structures of key proteins effectively and competitively, opening up ....X-ray diffraction System for Protein Crystallography and Structural Biology. Knowledge of protein structures enables researchers to explain cellular function at a molecular level. In particular, it provides essential information to understand the mechanism of diseases, such as cancer or AIDS, and it ultimately leads to the design of better drugs.
An in-house X-ray protein crystallography facility will allow us to determine the structures of key proteins effectively and competitively, opening up extensive possibilities for multi-disciplinary ground-breaking research.
The University research portfolio has evolved to embrace the revolution in structural biology with numerous projects and collaborations focusing on proteins involved in bacterial infections, degenerative disorders and biotechnological applications.Read moreRead less
The development of tools to study carbohydrate-processing enzymes implicated in human disease. Diseases caused by improper function of carbohydrate-processing enzymes are a major health burden. This research aims to find ways to restore the function of these enzymes bringing a better quality of life to people suffering from these diseases.
Understanding and exploiting bacterial sulfatases. Bacterial sulfatases participate in environmental nutrient cycling and are implicated in bacterial pathogenesis mechanisms. These enzymes catalyze the hydrolysis of sulfate esters and possess an unusual posttranslational active-site modification where a cysteine residue is oxidized to formylglycine. We will study the mechanism of these enzymes in detail and design inhibitors that exploit the reactivity of this aminoacid. This work has significan ....Understanding and exploiting bacterial sulfatases. Bacterial sulfatases participate in environmental nutrient cycling and are implicated in bacterial pathogenesis mechanisms. These enzymes catalyze the hydrolysis of sulfate esters and possess an unusual posttranslational active-site modification where a cysteine residue is oxidized to formylglycine. We will study the mechanism of these enzymes in detail and design inhibitors that exploit the reactivity of this aminoacid. This work has significance because of application to areas that include the treatment of cancer and bacterial infections. Additionally, we will clone novel carbohydrate sulfatases from the heparin-degrading bacterium Flavobacterium heparinum. These sulfatases will have use in biotechnology for characterization of sulfated glycoconjugates.Read moreRead less
Structural And Functional Studies On Glutamate Decarboxylase.
Funder
National Health and Medical Research Council
Funding Amount
$500,460.00
Summary
This proposal aims to determine the molecular structure of the two known isoforms of Glutamate Decarboxylase (GAD65 and GAD67). GAD in an essential human enzyme that is responsible for synthesising the primary inhibitory neurotransmitter gamma-aminobutyric acid (GABA). GABA functions in the human Central Nervous System (CNS) to dampen down excitatory signals. Proper control of GABA synthesis is important and perturbations in GABA levels lies behind human diseases such as intractable epilepsy, de ....This proposal aims to determine the molecular structure of the two known isoforms of Glutamate Decarboxylase (GAD65 and GAD67). GAD in an essential human enzyme that is responsible for synthesising the primary inhibitory neurotransmitter gamma-aminobutyric acid (GABA). GABA functions in the human Central Nervous System (CNS) to dampen down excitatory signals. Proper control of GABA synthesis is important and perturbations in GABA levels lies behind human diseases such as intractable epilepsy, depression and schizophrenia. As a result of this role, numerous common therapeutics (for example benzodiazepines) target proteins involved in the GABA neurotransmitter system. The goal of this proposal is to use the molecular structures of GAD to understand how to achieve fine control of GABA production. In addition to its role in the CNS, GAD is an important human autoantigen. Antibodies to one isoform of GAD, GAD65, are found in most patients with type I diabetes as well as certain patients with the movement disorder stiff person syndrome and related diseases of the CNS. It is suggested that the development of auto-antibodies may play a key role in the pathophysiology of these conditions. Despite sharing >80% sequence similarity with GAD65, autoantibodies to the other isoform of GAD, GAD67, are rarely found in patients with disease. The aim of this grant is to characterise the region of GAD that is targetted by autoantibodes. These data will allow us to understand why certain autoantibodes are able to inhibit GAD enzyme activity and why GAD65, but not GAD67 is recognised by autoantibodes.Read moreRead less
The Activation Of Lipoprotein Lipase By Apolipoprotein C-II
Funder
National Health and Medical Research Council
Funding Amount
$250,500.00
Summary
Abnormalities in blood lipid levels are common in our society. Treatment of these conditions adds a heavy burden to national health-care costs. Lipoprotein lipase is a plasma enzyme that plays a central role in maintaining safe blood lipid levels. The action of lipoprotein lipase in subjects on a western diet leads to the hydrolysis of about 150g of plasma triacylglycerol daily. Naturally occurring mutations in lipoprotein lipase, associated with a complete loss of enzyme activity, result in a h ....Abnormalities in blood lipid levels are common in our society. Treatment of these conditions adds a heavy burden to national health-care costs. Lipoprotein lipase is a plasma enzyme that plays a central role in maintaining safe blood lipid levels. The action of lipoprotein lipase in subjects on a western diet leads to the hydrolysis of about 150g of plasma triacylglycerol daily. Naturally occurring mutations in lipoprotein lipase, associated with a complete loss of enzyme activity, result in a high blood-lipids that can lead to premature atherosclerosis. Regulation of lipoprotein lipase occurs via an interaction with the regulatory protein apolipoprotein C-II. Individuals with apolipoprotein C-II deficiency also exhibit abnormal plasma lipid levels with an associated increased risk of coronary heart disease. These considerations demonstrate that the activation of lipoprotein lipase by apolipoprotein C-II is pivotal to the maintenance of normal blood lipid levels. The present proposal will establish the structure and orientation of apolipoprotein C-II in a lipid environment and provide a structural model for the activation of lipoprotein lipase by apolipoprotein C-II. These molecular details will serve as a model for the regulatory interactions of other apolipoproteins within lipoprotein particles and will generate leads for the development of new strategies for the treatment of blood lipid irregularities.Read moreRead less
New models of mitochondrial fatty acid oxidation disorders. Mitochondrial disease can affect both children and adults and is often fatal. This project will study mitochondrial function in cell types of the heart and brain to better understand how they generate energy in these tissues. This will provide new insights into mitochondrial metabolism and how defects in this process cause mitochondrial disease.
Inhibiting pathological signalling in haematopoietic disease. Certain leukaemias and other blood diseases are caused by the mutation of one particular molecule, called Janus Kinase (JAK), inside our bodies. This project aims to understand the biochemical details of these diseases by studying this mutated molecule in detail. The project will aim to provide the information for developing effective therapeutics against these diseases.
This project aims to investigate novel ways to treat children with the inherited brain disorder known as MPS IIIA. This condition is currently untreatable and children generally die in their teens. We will use a mouse model of this condition to examine the effectiveness of combining two different treatment approaches, in order to maximise outcomes.
Chemical inhibition: a new approach to investigate the role of a key protease, CtHtrA, from Chlamydia trachomatis. Infertility in women frequently results from infection with Chlamydia trachomatis. This project will develop an inhibitor compound against a important protein from this bacteria. This will establish a new scientific approach to study Chlamydia trachomatis. This project will also contribute to the development of new treatments for infertility.