Targeting Iron Piracy From Host Proteins By Neisseria And Haemophilus Spp. For The Development Of Novel Antimicrobials
Funder
National Health and Medical Research Council
Funding Amount
$645,205.00
Summary
The bacteria that cause the sexually transmitted infection gonorrhoea and meningococcal disease are a serious health concern. In order to cause disease, these bacteria must obtain the nutrient iron from our bodies. This proposed research will use cutting edge technologies to understand on a molecular level how these bacteria obtain iron during infection. It will then apply this knowledge to develop molecules that prevent these bacteria from obtaining iron, as a means of treating these diseases.
All in the family: understanding a new class of bacterial toxins. 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. The outcomes could reveal novel mechanisms general to these proteins and ....All in the family: understanding a new class of bacterial toxins. 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. 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. Read moreRead less
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
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
How do signals cross the cell membrane: the betacommon receptor family. This project aims to unravel missing molecular details of how a family of proteins, called the betacommon receptors, is able to signal across cell walls. This project aims to generate new knowledge about how membrane-bound receptors transmit biological signals in living organisms. Despite their fundamental importance in biology, how these proteins work remain enigmatic. Expected outcomes include discovery of novel mechanisms ....How do signals cross the cell membrane: the betacommon receptor family. This project aims to unravel missing molecular details of how a family of proteins, called the betacommon receptors, is able to signal across cell walls. This project aims to generate new knowledge about how membrane-bound receptors transmit biological signals in living organisms. Despite their fundamental importance in biology, how these proteins work remain enigmatic. Expected outcomes include discovery of novel mechanisms general to these types of protein receptors and fundamental insights in understanding vital physiological processes across all kingdoms of life. Ultimately, this new knowledge should benefit efforts to discover novel treatments in cases where malfunctioning receptors cause diseases in animals and humans.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE230101681
Funder
Australian Research Council
Funding Amount
$457,139.00
Summary
Cryo-electron microscopy determination of G protein-coupled receptor states. This project aims to address fundamental knowledge gaps in understanding of the molecular mechanisms of peptide hormone G protein-coupled receptor activation. This will be achieved through cryo-electron microscopy determination of the structure and dynamics of key intermediate states in activation. Novel biochemical approaches will be applied to capture these states, using as exemplar the glucagon receptor that has a br ....Cryo-electron microscopy determination of G protein-coupled receptor states. This project aims to address fundamental knowledge gaps in understanding of the molecular mechanisms of peptide hormone G protein-coupled receptor activation. This will be achieved through cryo-electron microscopy determination of the structure and dynamics of key intermediate states in activation. Novel biochemical approaches will be applied to capture these states, using as exemplar the glucagon receptor that has a broad range of pharmacological tools to facilitate isolation of distinct functional states. The knowledge gained from these studies will advance fundamental understanding of physiologically important receptor activation and efficacy, while the approaches developed will enable similar investigation of other receptor classes.Read moreRead less