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Phage display derived antibody fragments for membrane protein research. Membrane proteins are key components of all living organisms and represent more than 50 per cent of all drug targets. This project will redefine the way membrane proteins are studied and will be highly beneficial to basic research, human disease and the biotechnology industry.
Mastering pyrimidine editing in RNA. Many plants and animals can alter their genetic information via RNA (ribonucleic acid) editing, a process that is often essential for the growth and development of the organism. This ability provides accurate control over gene expression and has great potential as a biotechnological tool in agriculture and medicine. RNA editing could be used to switch genes on or off in biotechnological production systems with an unprecedented degree of precision, or to corre ....Mastering pyrimidine editing in RNA. Many plants and animals can alter their genetic information via RNA (ribonucleic acid) editing, a process that is often essential for the growth and development of the organism. This ability provides accurate control over gene expression and has great potential as a biotechnological tool in agriculture and medicine. RNA editing could be used to switch genes on or off in biotechnological production systems with an unprecedented degree of precision, or to correct genetic diseases. This project aims to understand two RNA editing pathways in plants, one of which is found nowhere else and likely to involve a novel enzymatic mechanism. We will use the understanding gained to develop novel RNA processing tools usable in any living organism.Read moreRead less
Engineering self-assembled intracellular biological condensates. Cells depend on proteins linking together to build cellular structure, but how weak interactions build stable structure is a mystery. New evidence suggests proteins come together and then change state, employing liquid-like behaviour that builds vital nanoscale structure, such as nuclear bodies called paraspeckles. This project will unlock the secrets of this mysterious behavior of proteins, using paraspeckles as a model. We will u ....Engineering self-assembled intracellular biological condensates. Cells depend on proteins linking together to build cellular structure, but how weak interactions build stable structure is a mystery. New evidence suggests proteins come together and then change state, employing liquid-like behaviour that builds vital nanoscale structure, such as nuclear bodies called paraspeckles. This project will unlock the secrets of this mysterious behavior of proteins, using paraspeckles as a model. We will use this information for nanotechnology application to build a synthetic paraspeckle inspired structure with bespoke function. Benefits will include new concepts in how vital cell structure is assembled and disassembled, and nanotechnology and synthetic biology tools to manipulate cellular processes.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE160100608
Funder
Australian Research Council
Funding Amount
$359,000.00
Summary
Investigating the structural basis of human antibody stability. This project plans to use protein engineering and X-ray crystallography to investigate the effects of stabilising mutations on antigen binding and the antibody-antigen interaction. Monoclonal antibodies are high-affinity reagents that have transformed the study of biological processes. However, antibodies often display inherent instability, which limits applicability. Mutations have recently been identified that render human antibod ....Investigating the structural basis of human antibody stability. This project plans to use protein engineering and X-ray crystallography to investigate the effects of stabilising mutations on antigen binding and the antibody-antigen interaction. Monoclonal antibodies are high-affinity reagents that have transformed the study of biological processes. However, antibodies often display inherent instability, which limits applicability. Mutations have recently been identified that render human antibodies resistant to aggregation. Preliminary data indicates that stabilising mutations improves the biophysical properties of monoclonals without affecting the native antibody structure. The project aims to provide detailed insights into the molecular basis of antibody stability.Read moreRead less
Investigating the dynamic nature of antibody stability. The aim of the project is to provide insights into the molecular mechanisms of antibody stability. Monoclonal antibodies have transformed the study of biological processes and represent blockbuster therapeutics for cancer and inflammation. Unfortunately, antibodies often display limited stability, which greatly hinders development. Mutations have recently been identified that render human antibodies resistant to aggregation, and high-resolu ....Investigating the dynamic nature of antibody stability. The aim of the project is to provide insights into the molecular mechanisms of antibody stability. Monoclonal antibodies have transformed the study of biological processes and represent blockbuster therapeutics for cancer and inflammation. Unfortunately, antibodies often display limited stability, which greatly hinders development. Mutations have recently been identified that render human antibodies resistant to aggregation, and high-resolution crystal structures are being used to identify function. Intriguingly, preliminary data indicates that the mutations do not affect the native antibody structure, but rather influence dynamic states. The project plans to use a combination of mutagenesis, molecular dynamics simulation and deuterium exchange to study antibody dynamics.Read moreRead less
Structural studies of a reconstructed primordial antigen receptor. Antigen receptors (B- and T-cell receptor) form the basis of the adaptive immune system of humans and all other modern day vertebrates. These complex receptors are believed to have evolved from an extinct homodimeric (symmetrical) ancestor through a process of gene duplication and diversification. However, any molecular insights had so far remained elusive. Using laboratory evolution and X-ray crystallography this project demonst ....Structural studies of a reconstructed primordial antigen receptor. Antigen receptors (B- and T-cell receptor) form the basis of the adaptive immune system of humans and all other modern day vertebrates. These complex receptors are believed to have evolved from an extinct homodimeric (symmetrical) ancestor through a process of gene duplication and diversification. However, any molecular insights had so far remained elusive. Using laboratory evolution and X-ray crystallography this project demonstrates that such a primordial receptor can in principle be reconstructed and characterised. The project proposes to expand this work, which will provide intriguing insights into antigen receptor evolution. The reconstruction of basic recognition modules will also be highly beneficial for biosensor applications. Read moreRead less
Artificially building the bacterial flagellar motor. This project will allow us to learn how nature’s most sophisticated rotary motor works and how to build these artificially, establishing a new field of research into man-made biological machines. This has potential applications for the emerging field of nanotechnology to make nanometre-scale devices that are powered by efficient biological machines.
IDENTIFYING CONTROL ELEMENTS IN CHLOROPLAST GENE EXPRESSION. Energy from sunlight is captured by photosynthesis in plants, providing the basis for the terrestrial food chain. This process takes place in chloroplasts, subcellular structures that derived from photosynthetic bacteria a billion years ago. Chloroplasts have their own DNA, containing genes encoding the most important photosynthetic proteins. This project aims to provide the world’s best resources for the study of chloroplast genes. In ....IDENTIFYING CONTROL ELEMENTS IN CHLOROPLAST GENE EXPRESSION. Energy from sunlight is captured by photosynthesis in plants, providing the basis for the terrestrial food chain. This process takes place in chloroplasts, subcellular structures that derived from photosynthetic bacteria a billion years ago. Chloroplasts have their own DNA, containing genes encoding the most important photosynthetic proteins. This project aims to provide the world’s best resources for the study of chloroplast genes. In the process, we will discover how these important genes are regulated to provide photosynthetic proteins in the right amounts, in the right cells, at the right time. The knowledge and resources gained will facilitate improvement of photosynthetic function in future agricultural crops.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE140100262
Funder
Australian Research Council
Funding Amount
$395,220.00
Summary
Artificial synthesis of bacteria's molecular syringe. The type III secretion system. The type III secretion system is an impressive protein superstructure consisting of hundreds of subunits that act cooperatively to specifically inject virulence factors directly into the cytoplasm of host cells. Its size and complexity make it a formidable challenge to understand at a molecular level with conventional methods. This project adopts a fundamentally new approach that will put Australian science in t ....Artificial synthesis of bacteria's molecular syringe. The type III secretion system. The type III secretion system is an impressive protein superstructure consisting of hundreds of subunits that act cooperatively to specifically inject virulence factors directly into the cytoplasm of host cells. Its size and complexity make it a formidable challenge to understand at a molecular level with conventional methods. This project adopts a fundamentally new approach that will put Australian science in the spotlight of a highly active research field. Artificial synthesis of bacteria's molecular syringe using DNA nanotechnology will revolutionise its study by providing unprecedented dexterity in its manipulation and, for the first time, allow the isolation of functional subcomplexes for high-resolution structural studies.Read moreRead less
A portable RNA-editing machine. Many plants maintain an elaborate RNA-editing machine that allows them to correct accumulated errors in their organellar genomes by specifically editing the RNA transcripts of the affected genes. A portable and adaptable version of this molecular machine would have significant biotechnological value, providing the ability to correct genetic errors, and to intervene in gene regulation without permanently altering a genome. The project aims to combine molecular and ....A portable RNA-editing machine. Many plants maintain an elaborate RNA-editing machine that allows them to correct accumulated errors in their organellar genomes by specifically editing the RNA transcripts of the affected genes. A portable and adaptable version of this molecular machine would have significant biotechnological value, providing the ability to correct genetic errors, and to intervene in gene regulation without permanently altering a genome. The project aims to combine molecular and structural biology approaches to fully characterise the components of the machine, thus allowing us to reconstitute it in cell-free systems and ultimately in other organisms.Read moreRead less