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
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
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE120100090
Funder
Australian Research Council
Funding Amount
$640,000.00
Summary
A centre for structural cryo-electron microscopy. This equipment will use powerful microscopes to visualise the shape of proteins. The data generated in the facility will provide fundamental insight into how large complex proteins govern life-and-death events in biology. These data will be important for scientists to develop new approaches to control aberrant protein function in disease.
The structural basis for MPEG1 mediated assembly of immune complexes. Macrophage Expressed Gene-1 (MPEG1) is an ancient pore forming perforin-like immune effector that is found throughout multicellular life. In humans MPEG1 is found in Macrophages (a type of immune cell) and functions to eliminate a wide range of different infectious microbes. In this study we will study how different modifications and molecular interactions drive MPEG1 function. Crucially our work will provide a framework to ....The structural basis for MPEG1 mediated assembly of immune complexes. Macrophage Expressed Gene-1 (MPEG1) is an ancient pore forming perforin-like immune effector that is found throughout multicellular life. In humans MPEG1 is found in Macrophages (a type of immune cell) and functions to eliminate a wide range of different infectious microbes. In this study we will study how different modifications and molecular interactions drive MPEG1 function. Crucially our work will provide a framework to understand how MPEG1 interacts with the interferon signalling pathway. These data will provide fundamental insight into how perforin-like proteins are controlled and will broadly inform new approaches to modify immune function and molecular signalling events.Read moreRead less
Structural analysis of poxviruses: advancing our understanding of complex DNA viruses and their in vivo crystals. This project will use innovative structural biology approaches to investigate two key particles of poxviruses, the largest viruses infecting humans. Advance in understanding of immature particles and natural crystals of poxviruses will provide the basis for the development of broad-spectrum antivirals and novel microparticles for vaccine-delivery.
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE120100152
Funder
Australian Research Council
Funding Amount
$360,000.00
Summary
Melbourne and La Trobe rapid integrated X-ray diffraction facility. This new facility will enable rapid X-ray diffraction studies of macromolecular crystals which are critical in reaching an understanding of cellular signalling events and interactions between microbial pathogens and their host organisms at the atomic level.
Understanding how pore-forming proteins punch holes in membranes. This project aims to unravel missing molecular details of how a major superfamily of proteins is able to drill holes in cell membranes. Animals, plants, fungi and bacteria all use pore-forming proteins as cell-killing weapons of mass destruction. Despite their lethal nature and their roles in infection and immunity, how these proteins work remains enigmatic. Project outcomes could reveal novel mechanisms general to these essential ....Understanding how pore-forming proteins punch holes in membranes. This project aims to unravel missing molecular details of how a major superfamily of proteins is able to drill holes in cell membranes. Animals, plants, fungi and bacteria all use pore-forming proteins as cell-killing weapons of mass destruction. Despite their lethal nature and their roles in infection and immunity, how these proteins work remains enigmatic. Project outcomes could reveal novel mechanisms general to these essential proteins and provide fundamental insights in understanding vital physiological processes across all kingdoms of life. Ultimately, the knowledge gained may prove useful in the engineering of membrane pores as highly specific sensors for a variety of molecules with nanotechnology and biotechnology applications.Read moreRead less
Pore-forming toxins: more than one way to make a hole. Animals, plants, fungi and bacteria all use pore-forming proteins as cell-killing weapons of mass destruction. Despite their lethal nature and their roles in infection and immunity, how these proteins work remains enigmatic. This project aims to unravel missing molecular details of how a major superfamily of such proteins is able to drill holes in cell membranes. The outcomes could reveal novel mechanisms general to these proteins and provid ....Pore-forming toxins: more than one way to make a hole. Animals, plants, fungi and bacteria all use pore-forming proteins as cell-killing weapons of mass destruction. Despite their lethal nature and their roles in infection and immunity, how these proteins work remains enigmatic. This project aims to unravel missing molecular details of how a major superfamily of such proteins is able to drill holes in cell membranes. The outcomes could reveal novel mechanisms general to these proteins and provide fundamental insights in understanding vital physiological processes across all kingdoms of life. Ultimately, this knowledge may guide the design of artificial protein pores that are selective for specific molecules with applications such as measuring metal ions, sugars, pesticides or pollutants.
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The structural basis for defensin-mediated membrane attack. This project aims to define how the innate defense proteins called defensins attack target membranes to cause cells to burst and die. It is often said that attack is the best form of defense, and the immune systems of plants and animals will often target the cell membranes of microbes and other pathogens to defend themselves. This project will identify the precise molecular mechanism underlying defensin activity, and clarify how ligand ....The structural basis for defensin-mediated membrane attack. This project aims to define how the innate defense proteins called defensins attack target membranes to cause cells to burst and die. It is often said that attack is the best form of defense, and the immune systems of plants and animals will often target the cell membranes of microbes and other pathogens to defend themselves. This project will identify the precise molecular mechanism underlying defensin activity, and clarify how ligand recognition and subsequent multimerisation leads to target membrane lysis. The project will establish the fundamental mechanisms regulating antimicrobial defense systems based on small proteins, and define a conceptual framework for the action of defensins to develop strategies to combat fungal infections.Read moreRead less
The structural biology of trace metal trafficking across membranes. This project aims to investigate how essential trace element nutrients are recognised and specifically acquired and expelled by bacterial cells. Cells are surrounded by biomembranes that separate and protect them from their environments. Embedded within these membranes are proteins that perform essential functions. In bacteria, membrane proteins are responsible for the uptake and elimination of trace elements that are required f ....The structural biology of trace metal trafficking across membranes. This project aims to investigate how essential trace element nutrients are recognised and specifically acquired and expelled by bacterial cells. Cells are surrounded by biomembranes that separate and protect them from their environments. Embedded within these membranes are proteins that perform essential functions. In bacteria, membrane proteins are responsible for the uptake and elimination of trace elements that are required for survival. This project will investigate the features of integral membrane proteins that allow discrimination between cargo, by defining their three dimensional architectures using X-ray crystallography. This will contribute to the field of membrane protein structural biology and fundamental discoveries in the area of cellular trace element homeostasis and toxicity.Read moreRead less