Structural studies of plant disease resistance proteins. Plant cells have evolved a gene-for-gene disease resistance mechanism, involving an interaction of a plant-derived receptor with a specific pathogen-derived molecule. Currently, plant breeders are restricted to the resistance genes available in particular crop species or sexually compatible relatives. In the last few years, several plant disease resistance genes have been identified, providing a foundation for studying the molecular basis ....Structural studies of plant disease resistance proteins. Plant cells have evolved a gene-for-gene disease resistance mechanism, involving an interaction of a plant-derived receptor with a specific pathogen-derived molecule. Currently, plant breeders are restricted to the resistance genes available in particular crop species or sexually compatible relatives. In the last few years, several plant disease resistance genes have been identified, providing a foundation for studying the molecular basis of the resistance process. We propose to obtain three-dimensional structural information on representative R proteins and their ligand complexes. This will form the basis for modifying existing resistance genes to confer resistance to new diseases, resulting in large economic benefits.Read moreRead less
Self organization in (bio)molecular systems: Simulating the folding and aggregation of peptides, proteins and lipids. Molecular self-assembly is a basic property of living systems. Most proteins fold spontaneously and then further self-organize into functional complexes, effectively biological machines. Understanding how this occurs is a fundamental theoretical challenge with widespread application. Work will focus on developing methodology to simulate, computationally, the folding and aggrega ....Self organization in (bio)molecular systems: Simulating the folding and aggregation of peptides, proteins and lipids. Molecular self-assembly is a basic property of living systems. Most proteins fold spontaneously and then further self-organize into functional complexes, effectively biological machines. Understanding how this occurs is a fundamental theoretical challenge with widespread application. Work will focus on developing methodology to simulate, computationally, the folding and aggregation of peptides, proteins, and lipids. The aim is to accurately predict the structures of small peptides in solution and to refine crude models of larger molecules (complexes). This will facilitate the development of peptide based therapeutics and is essential in exploiting the growing volume of genetic information in biology and medicine.Read moreRead less
Molecular Mechanisms of Biochemical Regulation: Neutron and X-ray Scattering Studies. This project will develop and use novel neutron and x-ray scattering methods to study the molecular mechanisms by which nature regulates biochemical processes. Healthy function requires cells to tightly control and coordinate a myriad of molecular activities. My research focuses on a set of interdependent molecular networks inside cells whose behavior is controlled by the so-called 'second messengers' that tr ....Molecular Mechanisms of Biochemical Regulation: Neutron and X-ray Scattering Studies. This project will develop and use novel neutron and x-ray scattering methods to study the molecular mechanisms by which nature regulates biochemical processes. Healthy function requires cells to tightly control and coordinate a myriad of molecular activities. My research focuses on a set of interdependent molecular networks inside cells whose behavior is controlled by the so-called 'second messengers' that translate external signals into the right cellular responses. The proposed experiments will provide a unique structural framework by which we can understand how these signals are transmitted. Such knowledge is an important foundation for advances in biomedical research and biotechnology applications.Read moreRead less
High resolution single particle analysis of biological macromolecules. One of the great challenges of cell biology is to increase the rate of atomic resolution structure determination, particularly of membrane proteins and macromolecular assemblies. The current rate-limiting step is high quality crystal production. Our goal is to prove that protein structures can be determined to atomic resolution by single-particle analysis. 3D structures will be produced by computationally aligning high-resolu ....High resolution single particle analysis of biological macromolecules. One of the great challenges of cell biology is to increase the rate of atomic resolution structure determination, particularly of membrane proteins and macromolecular assemblies. The current rate-limiting step is high quality crystal production. Our goal is to prove that protein structures can be determined to atomic resolution by single-particle analysis. 3D structures will be produced by computationally aligning high-resolution electron microscope images of individual, randomly oriented molecules. The importance of this project is highlighted by the fact over 120,000 protein sequences are already databased, a number set to increase rapidly as new genome sequencing projects are completed.
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DsbA: A target for the design of drug candidates as selective inhibitors of oxidative protein folding in Gram negative bacteria. There is a clear need for development of novel antibiotics which are capable of treating the increasingly prevalent strains of pathogenic bacteria that are resistant to currently available drugs. In this proposal we will design novel inhibitors of bacterial enzymes that are required for the correct folding of a variety of proteins and test the effects of these molecule ....DsbA: A target for the design of drug candidates as selective inhibitors of oxidative protein folding in Gram negative bacteria. There is a clear need for development of novel antibiotics which are capable of treating the increasingly prevalent strains of pathogenic bacteria that are resistant to currently available drugs. In this proposal we will design novel inhibitors of bacterial enzymes that are required for the correct folding of a variety of proteins and test the effects of these molecules on enzyme activity, bacterial growth and antibiotic resistance. Specific inhibitors of these enzymes constitute a novel strategy for the treatment of bacteria that have developed resistance to existing antimicrobial drugs.
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Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0237664
Funder
Australian Research Council
Funding Amount
$900,000.00
Summary
High Resolution Mass Spectrometer for (MS)n Chemical Characterisation. A Fourier transform ion cyclotron resonance ("FT-ICR") mass spectrometer equipped with electrospray ionisation (ESI) plus a "benchtop" matrix assisted laser desorption ionisation time of flight (MALDI-TOF) mass spectrometer are required to support the research of ca 28 research groups, including 44 postdoctoral fellows, and 138 honours and postgraduate students. By means of its high resolution and (MS)n capabilities, the FT- ....High Resolution Mass Spectrometer for (MS)n Chemical Characterisation. A Fourier transform ion cyclotron resonance ("FT-ICR") mass spectrometer equipped with electrospray ionisation (ESI) plus a "benchtop" matrix assisted laser desorption ionisation time of flight (MALDI-TOF) mass spectrometer are required to support the research of ca 28 research groups, including 44 postdoctoral fellows, and 138 honours and postgraduate students. By means of its high resolution and (MS)n capabilities, the FT-ICR-MS will provide key structural information on a wide range of synthetic and natural chemical substances, including sequence (e.g. peptides) and fragmentation patterns, while the MALDI-TOF instrument will be used primarily for high through-put proteomic analyses.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0560712
Funder
Australian Research Council
Funding Amount
$630,837.00
Summary
State-of-the-art biophysical tools for the characterisation of molecular interactions. In the current era of 'the genome' there is more demand than ever before for the characterisation of the gene products - the oligonucleotides and proteins that carry out the important functions in the cell. The current proposal is to acquire a suite of instrumentation to characterise the kinetics, thermodynamics and overall affinities of interactions between biological macromolecules and their physiological bi ....State-of-the-art biophysical tools for the characterisation of molecular interactions. In the current era of 'the genome' there is more demand than ever before for the characterisation of the gene products - the oligonucleotides and proteins that carry out the important functions in the cell. The current proposal is to acquire a suite of instrumentation to characterise the kinetics, thermodynamics and overall affinities of interactions between biological macromolecules and their physiological binding partners or with novel ligands. This will reveal the role of the macromolecules of interest in the cell, and potentially lead to the discovery of drug molecules which could interfere with molecular interactions underlying disease.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0989336
Funder
Australian Research Council
Funding Amount
$560,000.00
Summary
The South Australian Facility for Small and Large Molecule X-Ray Diffraction Structure Determination. The precise three dimensional arrangement of atoms within molecular and macromolecular structures defines their function. Thus, the discovery, development and application of biological compounds, catalysts, nanodevices and pharmaceuticals require X-ray diffraction structure determination. These endeavours underpin the conversion of academic research into real benefits for the community and are ....The South Australian Facility for Small and Large Molecule X-Ray Diffraction Structure Determination. The precise three dimensional arrangement of atoms within molecular and macromolecular structures defines their function. Thus, the discovery, development and application of biological compounds, catalysts, nanodevices and pharmaceuticals require X-ray diffraction structure determination. These endeavours underpin the conversion of academic research into real benefits for the community and are critical for the competitiveness of Australian industry, national productivity and economic growth. This application seeks to provide a facility for multidisciplinary scientific development that will enhance academic-industrial collaboration. This will position SA research community for scientific breakthroughs that benefit the Australian community.Read moreRead less
Structure and dynamics of a multiprotein-mRNA complex involved in the regulation of gene expression. RNA/protein interactions are now recognised as a major control point in the regulation of gene-expression. Proteins such as HuR and the poly(C)-binding proteins (PCBPs) act to stabilise and transport specific messenger (m)RNAs, and thus determine their translation levels. In contrast to such an important function, very little is known about these protein/mRNA interactions at an atomic level. The ....Structure and dynamics of a multiprotein-mRNA complex involved in the regulation of gene expression. RNA/protein interactions are now recognised as a major control point in the regulation of gene-expression. Proteins such as HuR and the poly(C)-binding proteins (PCBPs) act to stabilise and transport specific messenger (m)RNAs, and thus determine their translation levels. In contrast to such an important function, very little is known about these protein/mRNA interactions at an atomic level. The current study will investigate the structural and biophysical properties of a recently discovered HuR/PCBP/mRNA complex implicated in the regulation of androgen receptor expression. This information has the potential to assist in the development of drugs to reduce AR expression in prostate cancer.Read moreRead less
Optimisation of peptidic non-phosphorylated inhibitors of the Grb7 SH2 domain. The research outcomes will be of fundamental importance in the field of inhibitor development and as such will result in publications in high-profile international journals and continue to contribute to Australia's outstanding international reputation in biological research. Students and research associates that have the opportunity to work on this project will be trained in the use of state-of-the art technologies in ....Optimisation of peptidic non-phosphorylated inhibitors of the Grb7 SH2 domain. The research outcomes will be of fundamental importance in the field of inhibitor development and as such will result in publications in high-profile international journals and continue to contribute to Australia's outstanding international reputation in biological research. Students and research associates that have the opportunity to work on this project will be trained in the use of state-of-the art technologies in biochemistry, scientific rigour and presentation skills and thus contribute to the quality of our national workforce. Furthermore, applications that arise from this work will contribute to Australia's intellectual property and future developments in the pharmaceutical industry.Read moreRead less