Australian Laureate Fellowships - Grant ID: FL170100019
Funder
Australian Research Council
Funding Amount
$2,606,250.00
Summary
Proteins in motion - new tools for biotechnology. This project aims to assess the function of proteins by monitoring their motions using new nuclear magnetic resonance (NMR) spectroscopy techniques. As snapshots of 3D protein structures have been determined by crystallography, the new tools are designed to analyse functionally important motions in solution. A facility for ultrafast (> 100 kHz) magic angle spinning NMR spectroscopy of proteins in the semi-solid state will bring cutting-edge know- ....Proteins in motion - new tools for biotechnology. This project aims to assess the function of proteins by monitoring their motions using new nuclear magnetic resonance (NMR) spectroscopy techniques. As snapshots of 3D protein structures have been determined by crystallography, the new tools are designed to analyse functionally important motions in solution. A facility for ultrafast (> 100 kHz) magic angle spinning NMR spectroscopy of proteins in the semi-solid state will bring cutting-edge know-how to Australia and allow the interrogation of 3D structure and dynamics in selected protein regions. The expected outcomes of the project will have immediate benefits for the rational engineering of biocatalysts and in the design of lead compounds in drug development.Read moreRead less
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
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE180100026
Funder
Australian Research Council
Funding Amount
$178,839.00
Summary
Ultrafast magic angle spinning solid-state nuclear magnetic resonance capability. This project aims to extend an existing nuclear magnetic resonance (NMR) spectrometer for structural investigations of proteins in the solid state. Many proteins, such as amyloids and flexible proteins, cannot be studied by X-ray crystallography, solution NMR spectroscopy or cryoelectron microscopy, because they cannot be crystallised or are not sufficiently soluble, or are structurally too heterogeneous. This proj ....Ultrafast magic angle spinning solid-state nuclear magnetic resonance capability. This project aims to extend an existing nuclear magnetic resonance (NMR) spectrometer for structural investigations of proteins in the solid state. Many proteins, such as amyloids and flexible proteins, cannot be studied by X-ray crystallography, solution NMR spectroscopy or cryoelectron microscopy, because they cannot be crystallised or are not sufficiently soluble, or are structurally too heterogeneous. This project will extend the capability of an existing 800 MHz NMR spectrometer to solid-state NMR. By offering ultrafast magic angle spinning speeds, the system aims to afford greatly enhanced sensitivity and multidimensional NMR spectra of protein systems not previously amenable to structural analysis by NMR spectroscopy or other techniques. This will have important applications in biotechnology and biomedicine.Read moreRead less
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
Expanding the molecular tool set for structural studies of proteins and their complexes. Many applications in medical science and drug development depend on our ability to determine the 3D structures of proteins, protein assemblies and protein-ligand complexes. This project will develop novel lanthanide-binding tags and crosslinking agents that can be coupled to unnatural amino acids introduced into proteins with advanced protein chemistry techniques. These new tools will facilitate the collecti ....Expanding the molecular tool set for structural studies of proteins and their complexes. Many applications in medical science and drug development depend on our ability to determine the 3D structures of proteins, protein assemblies and protein-ligand complexes. This project will develop novel lanthanide-binding tags and crosslinking agents that can be coupled to unnatural amino acids introduced into proteins with advanced protein chemistry techniques. These new tools will facilitate the collection of structure restraints by nuclear magnetic resonance (NMR), electron paramagnetic resonance (EPR) and mass spectrometry, which are needed to generate accurate models of proteins and their complexes with other molecules. Major beneficial outcome will include an increase in the number of protein targets amenable to rational drug design and improved methods for generating new drug leads.Read moreRead less
Photosynthesis under extreme conditions. The aim of this project is to characterise modifications to the light dependent reactions of photosynthesis of simple, single cell organisms that live under harsh environmental conditions including: i) elevated temperature; ii) low, variable and low energy (red) light; iii) arid and variable hydration; and iv) chemical stress e.g. low pH. In a changing biosphere brought about by anthropological climate change, a better understanding of existing adaptions ....Photosynthesis under extreme conditions. The aim of this project is to characterise modifications to the light dependent reactions of photosynthesis of simple, single cell organisms that live under harsh environmental conditions including: i) elevated temperature; ii) low, variable and low energy (red) light; iii) arid and variable hydration; and iv) chemical stress e.g. low pH. In a changing biosphere brought about by anthropological climate change, a better understanding of existing adaptions of bacterial photosynthetic organisms may allow more resilient crops and other essential plants to be developed in the future. The project brings together an international consortium of world renowned experts across key aspects of photosynthesis. Read moreRead less
Selectively targeting cancer and infectious disease with fragment-based drug discovery. Finding better compounds as starting points is one of the major challenges for drug discovery research. Fragments are small, weak binding molecules that can be upsized into drug leads with better properties when compared to starting with larger molecules. This project addresses two weaknesses of current fragment based drug discovery (FBDD) methods: first, the limitations associated with screening fragments; a ....Selectively targeting cancer and infectious disease with fragment-based drug discovery. Finding better compounds as starting points is one of the major challenges for drug discovery research. Fragments are small, weak binding molecules that can be upsized into drug leads with better properties when compared to starting with larger molecules. This project addresses two weaknesses of current fragment based drug discovery (FBDD) methods: first, the limitations associated with screening fragments; and second, the quality of commercial fragment libraries. This project anticipates that the findings will establish a commanding role for both mass spectrometry and three-dimensional fragments in advancing FBDD approaches. It also expects to identify fragments with favourable development prospects towards the next generation of therapeutics.Read moreRead less