Drug discovery and structural biology by NMR spectroscopy. This project aims to extend the use of nuclear magnetic resonance (NMR) spectroscopy in rational drug development and protein structure analysis. A new chemical labelling approach provides detailed three-dimensional structure information of large protein-ligand complexes, needed for structure-based lead-compound development. New chemical and paramagnetic lanthanide tags for site-specific dual labelling of proteins will enhance this techn ....Drug discovery and structural biology by NMR spectroscopy. This project aims to extend the use of nuclear magnetic resonance (NMR) spectroscopy in rational drug development and protein structure analysis. A new chemical labelling approach provides detailed three-dimensional structure information of large protein-ligand complexes, needed for structure-based lead-compound development. New chemical and paramagnetic lanthanide tags for site-specific dual labelling of proteins will enhance this technology, which will assess target-drug interactions by in-cell electron paramagnetic resonance (EPR) spectroscopy. The techniques offer scope for accelerated drug development in the pharmaceutical industries.Read moreRead less
New methods for structural biology and drug discovery by nuclear magnetic resonance spectroscopy. Paramagnetic lanthanide tags offer fresh opportunities in structural biology and for rational drug design. Novel nuclear magnetic resonance (NMR) spectroscopy techniques will selectively detect the NMR signals from protein regions marked by paramagnetic lanthanides, accelerating the structure analysis of protein-ligand complexes. New lanthanide tags will bind to phosphoserine and selenocysteine resi ....New methods for structural biology and drug discovery by nuclear magnetic resonance spectroscopy. Paramagnetic lanthanide tags offer fresh opportunities in structural biology and for rational drug design. Novel nuclear magnetic resonance (NMR) spectroscopy techniques will selectively detect the NMR signals from protein regions marked by paramagnetic lanthanides, accelerating the structure analysis of protein-ligand complexes. New lanthanide tags will bind to phosphoserine and selenocysteine residues site-specifically introduced into proteins. These tags will also enable accurate distance measurements by electron paramagnetic resonance (EPR) spectroscopy in large, biologically important protein systems hitherto not amenable to detailed structural studies and in proteins undergoing conformational changes. Read moreRead less
The role of low-energy excited states in solar-energy capture. This project aims to determine the nature and role of the lowest-energy excited states in most natural photosynthetic reaction centres and light-harvesting complexes. The lowest-energy states of bacterial reaction centres are critical to function and are used as a paradigm in artificial organic solar-energy capture, but for most photosystems their nature remains unknown. The project aims to answer the critical question of why they do ....The role of low-energy excited states in solar-energy capture. This project aims to determine the nature and role of the lowest-energy excited states in most natural photosynthetic reaction centres and light-harvesting complexes. The lowest-energy states of bacterial reaction centres are critical to function and are used as a paradigm in artificial organic solar-energy capture, but for most photosystems their nature remains unknown. The project aims to answer the critical question of why they do not actually prevent function. It is expected that both the outcomes obtained and techniques developed will be directly relevant to solar-energy device design. The project will apply five existing, complimentary and purposely built spectrometers as well as quantum electronic and nuclear simulation techniques to identify and characterise three key systems.Read moreRead less
New methods for structure analysis of proteins and protein interactions. This project will advance nuclear magnetic resonance (NMR) technologies pioneered at the Australian National University which employ site-specific attachment of paramagnetic metal tags to proteins. A new and diverse set of strategies will dramatically extend the range of applications to targets of interest in the fight against cancer and bacterial infections.
Methods for Protein Structure Analysis by Electron Paramagnetic Resonance. This highly interdisciplinary project aims to establish new tools to analyse the structure and motions of proteins that are otherwise difficult to study. A combination of advanced biochemistry, modern magnetic spectroscopy methods, and high-performance computing techniques will be applied to study proteins at physiological concentrations and in complex environments. New techniques will be developed and tested on proteins ....Methods for Protein Structure Analysis by Electron Paramagnetic Resonance. This highly interdisciplinary project aims to establish new tools to analyse the structure and motions of proteins that are otherwise difficult to study. A combination of advanced biochemistry, modern magnetic spectroscopy methods, and high-performance computing techniques will be applied to study proteins at physiological concentrations and in complex environments. New techniques will be developed and tested on proteins of high biochemical or biomedical importance, and the approach will be applied to established drug targets.Read moreRead less
Three-dimensional structure determination of biomolecular assemblies from sparse data of different length scales. New computer algorithms will be combined with sparse experimental structure restraints, obtained with novel protein chemistry technologies, to generate accurate three-dimensional (3D) models of proteins and protein assemblies in solution and in the solid state. The new strategies will greatly increase the number of protein targets amenable to rational drug design.
Tags and algorithms for studies of protein structures and interactions. This project aims to develop a new set of tools to structurally characterise protein-protein and protein-ligand interactions that are difficult or impossible to analyse by other means, facilitate tracking of proteins in biological material and identify interaction partners. The project seeks to focus on the synthesis of new unnatural amino acids and tags for site-specific protein labelling, and a range of techniques for 3D s ....Tags and algorithms for studies of protein structures and interactions. This project aims to develop a new set of tools to structurally characterise protein-protein and protein-ligand interactions that are difficult or impossible to analyse by other means, facilitate tracking of proteins in biological material and identify interaction partners. The project seeks to focus on the synthesis of new unnatural amino acids and tags for site-specific protein labelling, and a range of techniques for 3D structure analysis in solution, in particular NMR spectroscopy. New algorithms are expected to be developed for optimizing NMR spectroscopy and structure calculations from sparse data. The integrated set of tools is expected to deliver better and faster structure analysis and target characterisation to accelerate early stages of drug discovery.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
Force-from-lipids biophysical principle underlying mechanotransduction. The major aim of this project is to determine evolutionary conserved physical principles of mechanotransduction in living cells through structure and function studies of PIEZO mechanoreceptor channels playing a crucial role in senses such as touch and pain in animals and humans. Mutations in these channels can cause numerous genetic disorders, including hereditary anaemias and joint contractures. Since they have been shown t ....Force-from-lipids biophysical principle underlying mechanotransduction. The major aim of this project is to determine evolutionary conserved physical principles of mechanotransduction in living cells through structure and function studies of PIEZO mechanoreceptor channels playing a crucial role in senses such as touch and pain in animals and humans. Mutations in these channels can cause numerous genetic disorders, including hereditary anaemias and joint contractures. Since they have been shown to respond to mechanical stimuli in the same manner as mechanoreceptor channels of organisms from bacteria to humans the intended outcome of this project is to uncover the unifying principles of mechanotransduction anchored in the laws of physics and chemistry that have guided the force-dependent design of all life forms.Read moreRead less
Non-Canonical Amino Acids for Protein Analysis and Peptide Inhibitors. This interdisciplinary project aims to establish new tools to experimentally confirm 3D structure predictions of proteins that are otherwise difficult to study. A combination of innovative biochemistry, modern spectroscopy, and high-performance computing will be applied to study protein-protein and protein-ligand interactions. The project expects to generate new techniques and to test them on established drug targets. Expecte ....Non-Canonical Amino Acids for Protein Analysis and Peptide Inhibitors. This interdisciplinary project aims to establish new tools to experimentally confirm 3D structure predictions of proteins that are otherwise difficult to study. A combination of innovative biochemistry, modern spectroscopy, and high-performance computing will be applied to study protein-protein and protein-ligand interactions. The project expects to generate new techniques and to test them on established drug targets. Expected outcomes include new tools which quickly inform medicinal chemists how drugs interact with their targets and how they can be improved. The developed tools should provide significant benefit to many researchers by accelerating the early stage of drug discovery, and support Australia’s fast growing biotechnology sector.Read moreRead less