Synthetic compounds to specifically activate or inhibit ryanodine receptor calcium ion channels. The aim of the project is develop synthetic compounds that specifically and reversibly activate or inhibit ryanodine receptor calcium release channels, and will thus increase or reduce the force developed by skeletal muscle and the heart. The compounds will be useful in biomedical and veterinary sciences and in the livestock industry. Some of the compounds that are not effective on mammalian ryan ....Synthetic compounds to specifically activate or inhibit ryanodine receptor calcium ion channels. The aim of the project is develop synthetic compounds that specifically and reversibly activate or inhibit ryanodine receptor calcium release channels, and will thus increase or reduce the force developed by skeletal muscle and the heart. The compounds will be useful in biomedical and veterinary sciences and in the livestock industry. Some of the compounds that are not effective on mammalian ryandine receptor isoforms might interact with insect channels and provide a template for a new class of insecticides. The compounds will be based on naturally occurring peptides which specifically and reversibly modulate mammalian calcium channels.Read moreRead less
3D Structure determination of biomacromolecular assemblies from sparse data. This project has direct impact on pharmaceutical research: Biomacromolecular interactions are key points for pharmaceutical intervention and detailed structural knowledge of dynamic protein interactions can significantly accelerate drug development. Australia has invested in expensive instrumentation that can be used with new laboratory methods to obtain information on delicately balanced biomacromolecular interactions, ....3D Structure determination of biomacromolecular assemblies from sparse data. This project has direct impact on pharmaceutical research: Biomacromolecular interactions are key points for pharmaceutical intervention and detailed structural knowledge of dynamic protein interactions can significantly accelerate drug development. Australia has invested in expensive instrumentation that can be used with new laboratory methods to obtain information on delicately balanced biomacromolecular interactions, and how they malfunction in disease. This project will provide a computational framework to increase the impact of this investment by integrating measurements from a range of novel technologies and developing understanding of changes in structure of large protein complexes in different functional states.Read moreRead less
Single Molecule Studies of Replisomal Function. It has recently become possible to watch the copying of DNA molecules with a specialized microscope in real time. This process requires assembly of a complex molecular machine on the DNA, followed by triggering of its function, and yields exquisitely detailed information about how the machine works. In this new collaboration between scientists in Australia and the U.S.A., we will assemble these machines on single DNA molecules, watch how they work ....Single Molecule Studies of Replisomal Function. It has recently become possible to watch the copying of DNA molecules with a specialized microscope in real time. This process requires assembly of a complex molecular machine on the DNA, followed by triggering of its function, and yields exquisitely detailed information about how the machine works. In this new collaboration between scientists in Australia and the U.S.A., we will assemble these machines on single DNA molecules, watch how they work and simultaneously measure the very small forces that the machines generate. This will give Australian scientists access to a new technology for studying molecular machines.Read moreRead less
New fragment-based drug design technology by NMR spectroscopy. A new nuclear magnetic resonance (NMR) spectroscopic strategy will be developed for rapid determination of the structure and binding mode of low-molecular weight compounds bound to target proteins. Structural information obtained in this way will greatly accelerate drug development by fragment-based drug design, and NMR spectroscopy is the only method that can deliver this information in solution at atomic resolution. The impact of t ....New fragment-based drug design technology by NMR spectroscopy. A new nuclear magnetic resonance (NMR) spectroscopic strategy will be developed for rapid determination of the structure and binding mode of low-molecular weight compounds bound to target proteins. Structural information obtained in this way will greatly accelerate drug development by fragment-based drug design, and NMR spectroscopy is the only method that can deliver this information in solution at atomic resolution. The impact of the project for pharmaceutical research is further enhanced by extending the range of proteins amenable to NMR analysis by the development of new labelling strategies using stable isotopes, lanthanides and an unnatural amino acid in a state-of-the-art protein production system.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE100100087
Funder
Australian Research Council
Funding Amount
$450,000.00
Summary
Regional Facility for Molecular Characterisation and Mapping. Researchers at the Schools of Chemistry at The Australian National University and University of Wollongong are involved in a range of projects where new molecules are synthesised or discovered in natural products such as rainforest plants and marine organisms. Some of the molecules have already shown promise against diseases such as Alzheimer's and cardiovascular disease. In order to fully characterise these molecules, two complementa ....Regional Facility for Molecular Characterisation and Mapping. Researchers at the Schools of Chemistry at The Australian National University and University of Wollongong are involved in a range of projects where new molecules are synthesised or discovered in natural products such as rainforest plants and marine organisms. Some of the molecules have already shown promise against diseases such as Alzheimer's and cardiovascular disease. In order to fully characterise these molecules, two complementary mass spectrometers, replacing ageing instrumentation will be commissioned at each site. In addition, researchers in Wollongong will acquire a MALDI mass spectrometer capable of imaging the distribution of molecules on tissues that may be pathologically important.Read moreRead less
How are plants responding to damage by oxidizing air pollutants? This project aims to obtain detailed understanding of the chemical processes by which the air pollutants ozone and nitrogen dioxide damage plants. Through an interdisciplinary approach involving physical organic chemistry and analytical biochemistry, this project intends to discover important reactions between plant biomolecules and air pollutants, identify biochemical mechanisms for pollution damage in crop model plants and reveal ....How are plants responding to damage by oxidizing air pollutants? This project aims to obtain detailed understanding of the chemical processes by which the air pollutants ozone and nitrogen dioxide damage plants. Through an interdisciplinary approach involving physical organic chemistry and analytical biochemistry, this project intends to discover important reactions between plant biomolecules and air pollutants, identify biochemical mechanisms for pollution damage in crop model plants and reveal the plant defence mechanism at the molecular level. Expected outcomes include the much-needed scientific foundations to support the development of more pollution-resilient crops in the future, ultimately enabling a breakthrough for the triple challenge of environmental pollution, climate change and food security.Read moreRead less
Dynamic Force Microscopy of small molecular assemblies. The possibility of manipulating a single molecule seems at first unreal, indeed 5 years ago it was pure science fiction. Through the gaining popularity of the Atomic Force Microscope (AFM) many perspectives about the molecular world are changing. Macroscopic effects such as adhesion and lubrication are now discussed in light of measurements made with this instrument. Newer work includes the observation of single protein unfolding experim ....Dynamic Force Microscopy of small molecular assemblies. The possibility of manipulating a single molecule seems at first unreal, indeed 5 years ago it was pure science fiction. Through the gaining popularity of the Atomic Force Microscope (AFM) many perspectives about the molecular world are changing. Macroscopic effects such as adhesion and lubrication are now discussed in light of measurements made with this instrument. Newer work includes the observation of single protein unfolding experiments. The biophysics oriented project detailed in this application will extend the AFM: into multi-molecular systems formed by self-assembly, such as cell membranes; into polyelectrolyte-surface interactions; and, finally into the sequencing of DNA.Read moreRead less
Directed evolution of enzymes for bioremediation: structure function studies of bimetalloenzymes. We will evolve enzymes that degrade organophosphate pesticides (OPs) that are used in Australian agriculture. Although these OPs were designed to kill insects they are closely related to chemical warfare agents and are known to be toxic to humans. Bacteria have acquired a number of enzymes that degrade some OPs. One such enzyme has been used in field trials demonstrating its potential to degrade OP ....Directed evolution of enzymes for bioremediation: structure function studies of bimetalloenzymes. We will evolve enzymes that degrade organophosphate pesticides (OPs) that are used in Australian agriculture. Although these OPs were designed to kill insects they are closely related to chemical warfare agents and are known to be toxic to humans. Bacteria have acquired a number of enzymes that degrade some OPs. One such enzyme has been used in field trials demonstrating its potential to degrade OP residues. However, many pesticides are not removed rapidly and OP-degrading enzymes require modification(s) if they are to be useful environmental reagents - this can be achieved with directed evolution. Read moreRead less
Molecular Interactions in the Eubacterial Replisome: A Paradigm for Study of Dynamic Macromolecular Machines. Many pathogenic bacteria have developed resistance to antibiotics in common use, and new drugs are urgently required to kill them. Copying of their chromosomes before they divide into two new cells is essential for bacteria to live, so DNA synthesis is a good process to target for development of new antibiotics. This project will use state-of-the-art equipment available in several labora ....Molecular Interactions in the Eubacterial Replisome: A Paradigm for Study of Dynamic Macromolecular Machines. Many pathogenic bacteria have developed resistance to antibiotics in common use, and new drugs are urgently required to kill them. Copying of their chromosomes before they divide into two new cells is essential for bacteria to live, so DNA synthesis is a good process to target for development of new antibiotics. This project will use state-of-the-art equipment available in several laboratories in Australia and overseas to develop new understanding of how the molecular machine that copies DNA works. This k nowledge could lead to new drugs, and will give us new information about how cellular machines function.Read moreRead less
Why is the photosynthetic CO2-fixing enzyme, Rubisco, so inefficient? Dissection of the catalytic chemistry by computational simulation and experimental testing. Fixation of CO2 by the enzyme Rubisco during photosynthesis produces organic compounds which feed all life. Despite this critical role, Rubisco catalyses its reaction sluggishly and, worse, discriminates poorly between CO2 and O2, leading to useless products. Our combined expertise equips us to analyse Rubisco's mechanism using quantum- ....Why is the photosynthetic CO2-fixing enzyme, Rubisco, so inefficient? Dissection of the catalytic chemistry by computational simulation and experimental testing. Fixation of CO2 by the enzyme Rubisco during photosynthesis produces organic compounds which feed all life. Despite this critical role, Rubisco catalyses its reaction sluggishly and, worse, discriminates poorly between CO2 and O2, leading to useless products. Our combined expertise equips us to analyse Rubisco's mechanism using quantum-chemical methods and then test predictions experimentally. We will capitalise on our previous successful studies of Rubisco by addressing emergent issues which are the keys to understanding catalytic efficiency and CO2/O2 selectivity: the roles of a carbamylated lysine; the way CO2 addition is rendered irreversible; and the spin inversion inherent in O2 addition.Read moreRead less