Functional evolution and therapeutic potential of snake venom coagulotoxins. This project aims to identify and understand the factors that influence the useful function of key residues (parts of larger compounds) in Australian snake venom coagulotoxins, which alter blood-clotting ability. In recent years, snake venom compounds have been demonstrated as useful models from which to synthesise therapeutic drugs to improve health and well-being. This project will test these important toxins on model ....Functional evolution and therapeutic potential of snake venom coagulotoxins. This project aims to identify and understand the factors that influence the useful function of key residues (parts of larger compounds) in Australian snake venom coagulotoxins, which alter blood-clotting ability. In recent years, snake venom compounds have been demonstrated as useful models from which to synthesise therapeutic drugs to improve health and well-being. This project will test these important toxins on model systems that represent natural prey items in order to determine the molecular and functional evolution of blood-clot forming enzymes. Expected outcomes include substantial contributions to the body of evolutionary biology knowledge, as well as narrowing the search for the ultimate drug candidates.Read moreRead less
Modulation of cellular metabolism by protein and peptide peroxides. Oxidation of peptides and proteins by a wide range of reactive radicals and other oxidants, in the presence of oxygen, generates protein peroxides. These species are now recognised to be key intermediates in both the deterioration of foods (e.g. development of rancidity and off-flavours, changes in colour and texture) and a number of human diseases, including cancer, heart disease and ageing. How these peroxides cause biological ....Modulation of cellular metabolism by protein and peptide peroxides. Oxidation of peptides and proteins by a wide range of reactive radicals and other oxidants, in the presence of oxygen, generates protein peroxides. These species are now recognised to be key intermediates in both the deterioration of foods (e.g. development of rancidity and off-flavours, changes in colour and texture) and a number of human diseases, including cancer, heart disease and ageing. How these peroxides cause biological perturbations is poorly understood. The proposed studies will provide valuable information as to how these peroxides affect cellular metabolism and provide key leads as to strategies which may prevent such damage.Read moreRead less
Mechanistic studies on the oxidation of amino acids, peptides and proteins and its biological consequences. Exposure of amino acids and proteins to radicals, oxidants, UV light, and metal ions results in oxidation, with consequent alteration to protein structure and function. It has been shown that these reactions occur during food spoilage, exposure of plants to excess UV light, and in a number of human diseases (e.g. heart disease and cancer). Despite evidence for a key role for protein oxidat ....Mechanistic studies on the oxidation of amino acids, peptides and proteins and its biological consequences. Exposure of amino acids and proteins to radicals, oxidants, UV light, and metal ions results in oxidation, with consequent alteration to protein structure and function. It has been shown that these reactions occur during food spoilage, exposure of plants to excess UV light, and in a number of human diseases (e.g. heart disease and cancer). Despite evidence for a key role for protein oxidation in these events, the fundamental chemistry and biochemistry of protein oxidation is incompletely understood. This is addressed in this project. Knowledge of the mechanisms of these reactions is a vital pre-requisite to the rational design of preventative strategies that might enhance food quality, minimise UV damage and enhance human health.Read moreRead less
The design and synthesis of angiotensin converting enzyme-2 (ACE2) inhibitors. A vast number of current drugs on the market are inhibitors of enzymes whose action needs to be controlled in order to treat many conditions. This proposal will apply our new approaches to the design of enzyme inhibitors with superior therapeutic action. The benefits of this research reside in new treatments for a range of cardiovascular diseases (the 3rd largest cause of mortality in Australia) and provide a platform ....The design and synthesis of angiotensin converting enzyme-2 (ACE2) inhibitors. A vast number of current drugs on the market are inhibitors of enzymes whose action needs to be controlled in order to treat many conditions. This proposal will apply our new approaches to the design of enzyme inhibitors with superior therapeutic action. The benefits of this research reside in new treatments for a range of cardiovascular diseases (the 3rd largest cause of mortality in Australia) and provide a platform for new biotech companies to be formed in Australia.Read moreRead less
Australian Laureate Fellowships - Grant ID: FL140100027
Funder
Australian Research Council
Funding Amount
$2,898,150.00
Summary
Under the hood: single-molecule studies of multi-protein machines. Under the hood: single-molecule studies of multi-protein machines. Living cells are filled with complex protein machines that are responsible for the molecular processes supporting life. This project is aimed towards the development of physical tools that enable the study of these protein complexes at the level of single molecules. This project aims to study the protein machinery responsible for DNA replication, the process of du ....Under the hood: single-molecule studies of multi-protein machines. Under the hood: single-molecule studies of multi-protein machines. Living cells are filled with complex protein machines that are responsible for the molecular processes supporting life. This project is aimed towards the development of physical tools that enable the study of these protein complexes at the level of single molecules. This project aims to study the protein machinery responsible for DNA replication, the process of duplicating genomic information before cell division. By making real-time single-molecule movies of the replication process, this project aims to unravel the molecular mechanisms of this important process and provide the knowledge required to understand disease mechanisms and catalyse drug development.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
Australian Laureate Fellowships - Grant ID: FL0992138
Funder
Australian Research Council
Funding Amount
$3,100,000.00
Summary
Towards antibacterials without resistance. Innovative automation technologies will be used to create and investigate a revolutionary new approach to disable pathogenic superbugs, bacteria resistant to multiple antibiotics. The chemicals created and proteins evaluated in this research program will advance fundamental knowledge about the molecular weapons that bacteria produce to cause disease; deliver social and economic benefits to Australia through the development of potential new antibacterial ....Towards antibacterials without resistance. Innovative automation technologies will be used to create and investigate a revolutionary new approach to disable pathogenic superbugs, bacteria resistant to multiple antibiotics. The chemicals created and proteins evaluated in this research program will advance fundamental knowledge about the molecular weapons that bacteria produce to cause disease; deliver social and economic benefits to Australia through the development of potential new antibacterial treatments; contribute to Australia's continued international leading role in drug discovery research; enhance international links and attract industry investment in Australia; and provide a stimulating research training environment to inspire and motivate the next generation of scientists.Read moreRead less
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
Snapshots of an enzyme in action: structural and mechanistic studies on the catalytic cycle of Escherichia coli ketol-acid reductoisomerase. Enzymes are required for almost every process that occurs in a living organism. For this reason, understanding how enzymes work is essential if we are to understand life itself. In this project we will investigate the enzyme KARI by capturing a series of snapshots of its atomic structure as it progresses through its working cycle. In addition, we will make ....Snapshots of an enzyme in action: structural and mechanistic studies on the catalytic cycle of Escherichia coli ketol-acid reductoisomerase. Enzymes are required for almost every process that occurs in a living organism. For this reason, understanding how enzymes work is essential if we are to understand life itself. In this project we will investigate the enzyme KARI by capturing a series of snapshots of its atomic structure as it progresses through its working cycle. In addition, we will make a series of small alterations to the atomic structure that will allow us to understand how the individual parts work together.Read moreRead less
Structure and inhibition of acetohydroxyacid synthase. Acetohydroxyacid synthase (AHAS) has been identified as the target for several widely used herbicides known as the sulfonylureas and imidazolinones. World-wide, these two herbicides account for $US2 billion in annual sales. The aim is to determine the three-dimensional structure of AHAS from several sources and in complex with these herbicides. Furthermore, AHAS appears to be an excellent target for the development of antibacterial compounds ....Structure and inhibition of acetohydroxyacid synthase. Acetohydroxyacid synthase (AHAS) has been identified as the target for several widely used herbicides known as the sulfonylureas and imidazolinones. World-wide, these two herbicides account for $US2 billion in annual sales. The aim is to determine the three-dimensional structure of AHAS from several sources and in complex with these herbicides. Furthermore, AHAS appears to be an excellent target for the development of antibacterial compounds and fungicides. Knowledge of the three dimensional structures of these enzymes will be important in the rational design of more effective inhibitors with improved selectivity.Read moreRead less