Beyond structure - solving conformational dynamics for intractable proteins. Proteins perform almost every task that enables the amazing complexity of cellular and whole organism physiology. These molecular machines perform this incredible array of tasks due to their ability to dynamically change shape. For the vast majority of these machines, we can only view a snapshot of the possible shapes they can adopt and can’t monitor how they change from one shape to another, which is critical for their ....Beyond structure - solving conformational dynamics for intractable proteins. Proteins perform almost every task that enables the amazing complexity of cellular and whole organism physiology. These molecular machines perform this incredible array of tasks due to their ability to dynamically change shape. For the vast majority of these machines, we can only view a snapshot of the possible shapes they can adopt and can’t monitor how they change from one shape to another, which is critical for their functioning. This project aims to develop and apply a completely new method to visualise dynamic changes in protein shape which is not possible with current techniques. This will allow us to provide a new description and understanding of the function of proteins, which is fundamental to all biology.Read moreRead less
Structure of the essential Commander protein trafficking complex. This project aims to provide a fundamental understanding of the structure and function of Commander, a large protein complex that controls export and recycling of internalised receptors. Commander is highly conserved throughout evolution and is essential for maintaining the homeostasis of hundreds of transmembrane receptors required for cell function and survival, regulating processes as diverse as lipid metabolism and cell adhesi ....Structure of the essential Commander protein trafficking complex. This project aims to provide a fundamental understanding of the structure and function of Commander, a large protein complex that controls export and recycling of internalised receptors. Commander is highly conserved throughout evolution and is essential for maintaining the homeostasis of hundreds of transmembrane receptors required for cell function and survival, regulating processes as diverse as lipid metabolism and cell adhesion. Despite advances in the understanding of Commander function, little is known about how Commander is assembled and interacts with other essential proteins. This project will use multidisciplinary cellular and structural biology approaches to reveal the architecture of Commander at an atomic level.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE240100931
Funder
Australian Research Council
Funding Amount
$453,237.00
Summary
Molecular insights into the allosteric regulation of opioid receptors. Allosteric regulation is the biological process by which molecules bind to proteins someplace other than their active site, regulating their activity. Proteins on the cell surface called membrane receptors can be allosterically regulated to fine-tune the response of cells to the environment. This project aims to investigate how small molecules regulate receptor activity at a molecular level, using opioid receptors as an exemp ....Molecular insights into the allosteric regulation of opioid receptors. Allosteric regulation is the biological process by which molecules bind to proteins someplace other than their active site, regulating their activity. Proteins on the cell surface called membrane receptors can be allosterically regulated to fine-tune the response of cells to the environment. This project aims to investigate how small molecules regulate receptor activity at a molecular level, using opioid receptors as an exemplar system. I will use an interdisciplinary approach that combines structural biology, medicinal chemistry, analytical pharmacology, and cell biology. The knowledge gained from these studies will advance fundamental understanding of receptor function and can lay the foundation for future drug discovery efforts.Read moreRead less
Understanding T cell trafficking and function during antigenic interference. Science generally studies antigenic stimulation in isolation, by measuring immunity towards antigens derived from a single pathogen. However, as mammals can harbour more than one infection at any given time, we established a model of antigenic interference using different antigens derived from two unrelated pathogens, influenza A (IAV) and Semliki Forest virus (SFV). Our data show that prior exposure to either IAV or SF ....Understanding T cell trafficking and function during antigenic interference. Science generally studies antigenic stimulation in isolation, by measuring immunity towards antigens derived from a single pathogen. However, as mammals can harbour more than one infection at any given time, we established a model of antigenic interference using different antigens derived from two unrelated pathogens, influenza A (IAV) and Semliki Forest virus (SFV). Our data show that prior exposure to either IAV or SFV greatly perturbs T cell dynamics. This proposal will study, at cellular and molecular levels, T cell trafficking, function and clonal distribution during antigenic interference, thus advance fundamental knowledge on T cell immunity during antigenic competition, and provide a new paradigm on how we research T cell immunity.Read moreRead less
The Role of Lck/CD8 Association in Negatively Regulating T cell Activation. This proposal aims to advance our fundamental understanding of how T cell recognition of antigens translates into a T cell activating signal. The proposal will establish whether the major T cell coreceptor also acts as a negative regulator of T cell activation in vivo when antigen recognition is unorthodox. It will also determine whether certain subsets of T cells naturally lack coreceptors in order to facilitate unortho ....The Role of Lck/CD8 Association in Negatively Regulating T cell Activation. This proposal aims to advance our fundamental understanding of how T cell recognition of antigens translates into a T cell activating signal. The proposal will establish whether the major T cell coreceptor also acts as a negative regulator of T cell activation in vivo when antigen recognition is unorthodox. It will also determine whether certain subsets of T cells naturally lack coreceptors in order to facilitate unorthodox antigen recognition. Thus, the proposal will significantly advance our understanding of, and establish new paradigms around, the regulation of T cell activation. Expected long term benefits outside the scope of this proposal include improved immunotherapies and vaccines designed to elicit or suppress T cell responses.Read moreRead less
The functional architecture of a unique family of lipid droplet proteins. Eukaryotic cells are distinguished by the presence of membrane-bound compartments called organelles. This project will use structural biology to determine how essential proteins called sorting nexins (SNXs) regulate membrane interactions required for lipid droplet formation. These interactions are essential for life, controlling protein and lipid homeostasis needed for cell survival. The major outcome of this proposal will ....The functional architecture of a unique family of lipid droplet proteins. Eukaryotic cells are distinguished by the presence of membrane-bound compartments called organelles. This project will use structural biology to determine how essential proteins called sorting nexins (SNXs) regulate membrane interactions required for lipid droplet formation. These interactions are essential for life, controlling protein and lipid homeostasis needed for cell survival. The major outcome of this proposal will be a fundamental understanding of how SNXs control this process, and the work will significantly strengthen our international collaboration in this emerging area. The knowledge has potential future translation in the treatment of neurodegenerative disorders where dysregulation of these proteins is known to cause disease. Read moreRead less
Tuning the activating stimulus of voltage-gated sodium channels. This proposal aims to advance fundamental knowledge about how proteins (ion channels) found on the surface of neurons (brain cells and nerves) function as molecular conduits of cell-to-cell electrical communication. We aim to study how molecular probes and structural parts of these proteins affect the local chemical environment of ion channels, and how this leads to fine tuning of the ion channel's sensitivity to the stimulus that ....Tuning the activating stimulus of voltage-gated sodium channels. This proposal aims to advance fundamental knowledge about how proteins (ion channels) found on the surface of neurons (brain cells and nerves) function as molecular conduits of cell-to-cell electrical communication. We aim to study how molecular probes and structural parts of these proteins affect the local chemical environment of ion channels, and how this leads to fine tuning of the ion channel's sensitivity to the stimulus that activates them (cell membrane voltage).
The conceptual knowledge gained from this project would advance our understanding of a fundamental physiological process and facilitate the development of drugs that regulate ion channel function, such as anti-epileptics, analgesics and insecticides.Read moreRead less
The physiological importance of GLP-1R and GIPR dimerisation. Cell surface receptors are vital for relaying information from hormones to the cell to influence cell function, and ultimately physiological responses. Receptors can form oligomers with other receptors, but whether this can influence cellular and physiological responses is not yet defined. This biology-based project aims to bridge this knowledge gap by studying the dimerisation between two related receptors involved in whole body meta ....The physiological importance of GLP-1R and GIPR dimerisation. Cell surface receptors are vital for relaying information from hormones to the cell to influence cell function, and ultimately physiological responses. Receptors can form oligomers with other receptors, but whether this can influence cellular and physiological responses is not yet defined. This biology-based project aims to bridge this knowledge gap by studying the dimerisation between two related receptors involved in whole body metabolic homeostasis. Our team will deliver new knowledge into the disciplines of pharmacology, cellular biology, metabolism and physiology, and provide interdisciplinary research training to students and junior scientists, and strengthen research collaboration within and outside of Australia.Read moreRead less
Structure and dynamics of class B1 G protein coupled receptors . Cells within our body require cell surface proteins (receptors) to convert extracellular stimuli into an appropriate biological response. G protein-coupled receptors are the largest group of cell surface receptors. This project focuses on a subset of these receptors that have diverse and important functions in the central nervous system and the periphery, however there are many unanswered questions regarding the structure of these ....Structure and dynamics of class B1 G protein coupled receptors . Cells within our body require cell surface proteins (receptors) to convert extracellular stimuli into an appropriate biological response. G protein-coupled receptors are the largest group of cell surface receptors. This project focuses on a subset of these receptors that have diverse and important functions in the central nervous system and the periphery, however there are many unanswered questions regarding the structure of these proteins, and how they regulate cellular signalling. The primary outcomes of this project will provide detailed mechanistic insights on how receptors bind their stimuli and how this results in in their activation to mediate fundamental signalling that is important for all living organisms.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