Regulation of cell surface sialylation by targeting the CMP-sialic acid transporter and sialyltransferase: Towards the development of anti-metastatic agents. The mortality rates for many of the cancers afflicting the world's population are mirrored in Australia, particularly colon cancer. It's generally accepted that colon cancer, and cancers as a whole, are a significant healthcare issue in this country, representing a major challenge to biomedical researchers and healthcare professional. The e ....Regulation of cell surface sialylation by targeting the CMP-sialic acid transporter and sialyltransferase: Towards the development of anti-metastatic agents. The mortality rates for many of the cancers afflicting the world's population are mirrored in Australia, particularly colon cancer. It's generally accepted that colon cancer, and cancers as a whole, are a significant healthcare issue in this country, representing a major challenge to biomedical researchers and healthcare professional. The economic and social impact is immense, placing a huge strain on the healthcare system, as well as on the families affected. Any alternative treatment reducing cancer metastasis would be of enormous national and international benefit. It's believed that the significant studies outlined in this proposal, which are based on exciting preliminary data, will make a sizeable contribution to achieving this goal.Read moreRead less
Molecular analysis of glutathione transferase interactions with drugs and physiological ligands. Proteins called glutathione transferases protect us from toxic molecules that we ingest, breathe in or are by-products of normal metabolism. The same proteins also bind to many types of drugs leading them to be excreted from the body. In this project molecular structures of glutathione transferases bound to anti-cancer drugs will be determined as the basis for devising inhibitors of the protein that ....Molecular analysis of glutathione transferase interactions with drugs and physiological ligands. Proteins called glutathione transferases protect us from toxic molecules that we ingest, breathe in or are by-products of normal metabolism. The same proteins also bind to many types of drugs leading them to be excreted from the body. In this project molecular structures of glutathione transferases bound to anti-cancer drugs will be determined as the basis for devising inhibitors of the protein that will make drugs much more effective.Read moreRead less
Structural studies of glutathione transferases: a model system for functional genomics and drug design. Glutathione S-transferases (GSTs) are a large family of multi-functional proteins that play a vital role in an organism's defence against toxic chemicals. However, they also attack a variety of drugs and hence are a prime target for the development of isoform-specific inhibitors. We will determine the 3D atomic structures of GSTs in complex with a range of substrates and inhibitors as a basis ....Structural studies of glutathione transferases: a model system for functional genomics and drug design. Glutathione S-transferases (GSTs) are a large family of multi-functional proteins that play a vital role in an organism's defence against toxic chemicals. However, they also attack a variety of drugs and hence are a prime target for the development of isoform-specific inhibitors. We will determine the 3D atomic structures of GSTs in complex with a range of substrates and inhibitors as a basis for the design of compounds to improve the efficacy of anti-cancer and other drugs. This is an ambitious, wide-ranging project involving collaborators around the world. We expect the results will not only greatly increase our knowledge of an important enzyme family, but will also have applications in protein folding, catalysis, protein engineering, evolution, drug design and functional genomics. Read moreRead less
Cellular Responses to Adversity: Oxidative Stress and Protection Against Oxidative Damage. A deficiency in the protein haem oxygenase-1 causes severe biological consequences in animals and humans. These include decreased reproduction, retarded development, the inability of the body to handle iron, chronic inflammation and increased susceptibility to age-associated diseases. This study will determine how a deficiency of the protein alters cells at the level of genes, proteins and protein function ....Cellular Responses to Adversity: Oxidative Stress and Protection Against Oxidative Damage. A deficiency in the protein haem oxygenase-1 causes severe biological consequences in animals and humans. These include decreased reproduction, retarded development, the inability of the body to handle iron, chronic inflammation and increased susceptibility to age-associated diseases. This study will determine how a deficiency of the protein alters cells at the level of genes, proteins and protein functions. By doing so, the project will illuminate how haem oxygenase-1 alters cell functions in a beneficial way. This information will eventually assist in preventing the serious disorders associated with deficiency of haem oxygenase-1. It will also provide the basis for novel treatments to slow down age-associated diseases.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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Structure, Assembly, And Inhibition Of The Human Telomerase Enzyme Complex
Funder
National Health and Medical Research Council
Funding Amount
$645,359.00
Summary
In contrast to the limited growth of normal human cells, cancer cells proliferate out of control and without limit. At least 85% of all human cancers rely on the enzyme TELOMERASE to sustain their unlimited proliferation. Telomerase is absent in most normal tissues and therefore represents a potentially effective and specific target for future cancer therapy. We aim to determine the precise 3-dimensional shape of human telomerase to provide a template for rational anti-telomerase drug design.
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
Understanding and Inhibiting the P450 CYP24 enzyme, a target for cancer chemotherapeutics. This project falls within the National Research Priority of Promoting and Maintaining Good Health in the category of ageing well and productively. CYP24 inhibition provides a particular target for breast and prostate cancer which are the second leading cause of death in women and men, respectively. The proposed research will result in the production of CYP24 inhibitors that will be assessed in vivo at th ....Understanding and Inhibiting the P450 CYP24 enzyme, a target for cancer chemotherapeutics. This project falls within the National Research Priority of Promoting and Maintaining Good Health in the category of ageing well and productively. CYP24 inhibition provides a particular target for breast and prostate cancer which are the second leading cause of death in women and men, respectively. The proposed research will result in the production of CYP24 inhibitors that will be assessed in vivo at the Hanson Institute in Adelaide as potential anti-cancer drugs. Finally, there is a significant benefit in technology transfer to Australia from our collaborators in the USA in the field of computer aided inhibitor design.Read moreRead less
A new Src, PKCdelta and Akt regulated protease activated receptor system in metastasis. In contrast with localised cancer which can often be cured, curative treatment is generally not possible for cancer that has spread. This project will characterise a protein that drives the spread of cancer and to develop new approaches to treat patients at risk of developing these aggressive tumours that spread to other organs.