Discovery Early Career Researcher Award - Grant ID: DE200101323
Funder
Australian Research Council
Funding Amount
$427,098.00
Summary
Structure guided mapping of protein interactions and their perturbation. Protein interactions are central to most biological processes, and significant effort has been devoted to trying to unravel these complicated networks. This project aims to develop new approaches to better understand these interactions, and the consequences of their perturbation. The main expected contributions will be: (i) methods to identify likely protein interaction sites using population conservation; (ii) computationa ....Structure guided mapping of protein interactions and their perturbation. Protein interactions are central to most biological processes, and significant effort has been devoted to trying to unravel these complicated networks. This project aims to develop new approaches to better understand these interactions, and the consequences of their perturbation. The main expected contributions will be: (i) methods to identify likely protein interaction sites using population conservation; (ii) computational approaches to assess the effects of any type of mutation on the interaction; and (iii) an understanding of how disruption of a specific interaction can affect the complicated biological network within a cell. Read moreRead less
Connecting the dots: Image analysis for single molecule localisation microscopy. It is now possible to record the positions of single fluorescent molecules in intact cells to build up an image literally molecule by molecule. But how to ‘connect the dots’ and extract structural information from molecular coordinates is yet to be worked out. The project aims to do exactly that, and write and implement novel analysis routines to quantify a diverse range of biological structures such as protein comp ....Connecting the dots: Image analysis for single molecule localisation microscopy. It is now possible to record the positions of single fluorescent molecules in intact cells to build up an image literally molecule by molecule. But how to ‘connect the dots’ and extract structural information from molecular coordinates is yet to be worked out. The project aims to do exactly that, and write and implement novel analysis routines to quantify a diverse range of biological structures such as protein complexes, membrane morphologies, filamentous cytoskeletal networks, vesicles and viruses. The project is a collaboration between a cell biologist (Professor Gaus) who is a leader in single molecule localisation microscopy, an expert in fluorescence image analysis (Dr Nicovich) and an industry partner (Dr Lucas) who has a sophisticated software platform.Read moreRead less
New methods for drug discovery by NMR spectroscopy. This project aims to advance nuclear magnetic resonance (NMR) spectroscopy methods in the field of drug discovery. It addresses a long-standing bottleneck for medicinal chemists in drug development: the rapid determination of how ligand molecules bind to proteins, where they bind and their orientation in the binding site. The methods include techniques for the attachment of NMR tags to ligands and target proteins, installation of new unnatural ....New methods for drug discovery by NMR spectroscopy. This project aims to advance nuclear magnetic resonance (NMR) spectroscopy methods in the field of drug discovery. It addresses a long-standing bottleneck for medicinal chemists in drug development: the rapid determination of how ligand molecules bind to proteins, where they bind and their orientation in the binding site. The methods include techniques for the attachment of NMR tags to ligands and target proteins, installation of new unnatural amino acids in proteins, and software for automated assignment of NMR spectra and 3D structure modelling of proteins using sparse distance restraints measured by electron paramagnetic resonance (EPR) spectroscopy. The outcome is to benefit the early stages of drug discovery in the biotech industries.Read moreRead less
Single cell imaging of trace elements by laser ablation - inductively coupled plasma - mass spectrometry. The precise mechanism of how many diseases function on the cellular level is not well understood. Trace elements are important to normal cellular function and have the potential to cause significant damage if delicate levels are disturbed. This project will introduce a new, cost-effective alternative to the synchrotron for mapping of trace elements in single cells. This breakthrough science ....Single cell imaging of trace elements by laser ablation - inductively coupled plasma - mass spectrometry. The precise mechanism of how many diseases function on the cellular level is not well understood. Trace elements are important to normal cellular function and have the potential to cause significant damage if delicate levels are disturbed. This project will introduce a new, cost-effective alternative to the synchrotron for mapping of trace elements in single cells. This breakthrough science will transform a common analytical instrument into a powerful new tool for probing the cellular mechanisms of chronic illness. This frontier technology will help determine the role of trace metals in the development of neurodegenerative disease.Read moreRead less
Structural studies of host-pathogen interactions. The host-pathogen interface represents a major frontier for biomedical and biotechnological applications. This project aims to understand at the atomic level two such interfaces. In the first instance, the project will elucidate the molecular basis for inhibition of premature host cell death by poxviruses, in particular vaccinia and variola virus, the causative agent of smallpox. In the second instance, the aim is to understand how defensins, a ....Structural studies of host-pathogen interactions. The host-pathogen interface represents a major frontier for biomedical and biotechnological applications. This project aims to understand at the atomic level two such interfaces. In the first instance, the project will elucidate the molecular basis for inhibition of premature host cell death by poxviruses, in particular vaccinia and variola virus, the causative agent of smallpox. In the second instance, the aim is to understand how defensins, a major class of host defence molecules, recognise microbial targets such as fungi, and exert a potent antimicrobial effect. Understanding the precise molecular mechanisms operating at both these host-pathogen interfaces this will provide novel avenues for the design of antiviral and antimicrobial agents.Read moreRead less
Computational enzymology: exploring the free energy landscape of enzymatic catalysis. Most biochemical reactions depend on enzyme catalysis and understanding how enzymes work at the molecular level remains a central question. This project will develop a suite of computational models to study the mechanisms of enzyme-catalysed reactions and such knowledge holds promise for technological benefits in the form of new drugs and novel catalysts.
Engineering new tools to aid structure determination of membrane proteins. This project aims to address the inherent instability of G protein-coupled receptors (GPCRs), which are cell-surface proteins that are a major drug targets. The instability of GPCRs has resulted in a lack of atomic-level structural information that has hindered structure-based drug discovery efforts. This project expects to develop tools to improve GPCR stability and streamline the structure determination process. Project ....Engineering new tools to aid structure determination of membrane proteins. This project aims to address the inherent instability of G protein-coupled receptors (GPCRs), which are cell-surface proteins that are a major drug targets. The instability of GPCRs has resulted in a lack of atomic-level structural information that has hindered structure-based drug discovery efforts. This project expects to develop tools to improve GPCR stability and streamline the structure determination process. Project outcomes are intended to lead to significant advances in membrane protein structure determination and will have a substantial impact on future research in the pharmaceutical industry.Read moreRead less
Protein structure controls light harvesting in photosynthetic light algae. The strange phenomena of quantum mechanics were not expected to play a direct role in life, however, it appears that quantum effects may be important in the efficient capture of sunlight for photosynthesis. The conditions for the emergence of quantum phenomena appear to be set by the structures of proteins. The aim of this project is to relate protein structure to the emergence of quantum effects in the light harvesting p ....Protein structure controls light harvesting in photosynthetic light algae. The strange phenomena of quantum mechanics were not expected to play a direct role in life, however, it appears that quantum effects may be important in the efficient capture of sunlight for photosynthesis. The conditions for the emergence of quantum phenomena appear to be set by the structures of proteins. The aim of this project is to relate protein structure to the emergence of quantum effects in the light harvesting proteins of marine algae. Understanding the link between structure and quantum effects could improve our knowledge of how nature achieves its remarkable efficiency in utilising the energy from the sun. This is likely to foster new technologies that improve the efficiency of solar energy systems.Read moreRead less