Bacterial antibiotic resistance is mediated through specific biological molecules, so-called multidrug transporter proteins, which effectively export drugs from the cell. This proposal aims to solve the 3D structure of a multidrug resistance protein, NorM, which confers resistance to fluoroquinolone type drugs. Through this, we will provide detail into transport across the membrane of cells, and thus present a molecular understanding of bacterial antibiotic resistance.
Investigation Of Biological Ion Channels: Theoretical Formulation, Computer Simulation And Experimental Verification
Funder
National Health and Medical Research Council
Funding Amount
$677,292.00
Summary
All electrical activities in the brain are regulated by opening and closing of ion channels. Thus, undertanding their mechanisms at a molecular level is a fundamental problem in neurobiology. There are many different types of ion channels, each type fulfilling a different role. For the first time, a group of American scientists have determined the shape of one type of ion channels. Using this newly unveiled information, we propose to build a mathematical theory of ion channels. And then, making ....All electrical activities in the brain are regulated by opening and closing of ion channels. Thus, undertanding their mechanisms at a molecular level is a fundamental problem in neurobiology. There are many different types of ion channels, each type fulfilling a different role. For the first time, a group of American scientists have determined the shape of one type of ion channels. Using this newly unveiled information, we propose to build a mathematical theory of ion channels. And then, making use of a powerful supercomputer, we propose to follow the motion of ions as they move through the channel, study how a channel can select only the correct type of ions to traverse it and determine how many ions a single channel is capable of processing per second. The predictions made by our theory and computer simulations will be checked experimentally. If the predictions and experimental findings do not agree, we will modify the theory and make new predictions.Read moreRead less
A rational approach to a high-resolution structure of the multidrug transporter EmrE. Membrane proteins form only 0.3% of the available protein structures in the protein data bank (PDB), yet 30% of the proteins in the human genome and 50% of human drug targets are membrane proteins. Multidrug transporters are membrane proteins responsible for antibiotic resistance in humans. A high-resolution structure of a multidrug resistance protein, together with comprehensive biochemical characterization, w ....A rational approach to a high-resolution structure of the multidrug transporter EmrE. Membrane proteins form only 0.3% of the available protein structures in the protein data bank (PDB), yet 30% of the proteins in the human genome and 50% of human drug targets are membrane proteins. Multidrug transporters are membrane proteins responsible for antibiotic resistance in humans. A high-resolution structure of a multidrug resistance protein, together with comprehensive biochemical characterization, would enable a detailed understanding of how these protein functions. Potentially it could also aid in the development of specific inhibitors that would prevent EmrE (and perhaps other similar proteins) from carry out its harmful mission. Read moreRead less
Mechanosensitive properties and modulation of N-methyl-D-aspartate (NMDA) receptors by lipid environment. This project will provide new information about the molecular determinants which influence NMDA receptor channel gating that will significantly advance our understanding of a link between NMDA receptor function and many neurodegenerative diseases as well as pain and learning and memory. The outcomes of this project may lead to the discovery of novel lipid-based biomaterials for application i ....Mechanosensitive properties and modulation of N-methyl-D-aspartate (NMDA) receptors by lipid environment. This project will provide new information about the molecular determinants which influence NMDA receptor channel gating that will significantly advance our understanding of a link between NMDA receptor function and many neurodegenerative diseases as well as pain and learning and memory. The outcomes of this project may lead to the discovery of novel lipid-based biomaterials for application in medicine and the drug industry. This research is highly significant in relation to human health. The biological and nutritional aspects of polyunsaturated lipids and dietary fish oils have long been recognized. Thus this project will provide further knowledge that could benefit the health of the nation with consequent reduced health care costs.Read moreRead less
Disorder as a novel determinant of photosynthetic structure and function: an experimental study. Australia enjoys a world reputation in photosynthesis research, typified by hosting the 2001 International Photosynthesis Congress. It also has a claim to fame for theoretical work in non-equilibrium thermodynamics concerning production of disorder or entropy, yielding new insights into planetary climates. This experimental project investigates the novel relation between entropy/entropy production ....Disorder as a novel determinant of photosynthetic structure and function: an experimental study. Australia enjoys a world reputation in photosynthesis research, typified by hosting the 2001 International Photosynthesis Congress. It also has a claim to fame for theoretical work in non-equilibrium thermodynamics concerning production of disorder or entropy, yielding new insights into planetary climates. This experimental project investigates the novel relation between entropy/entropy production and the structure/function of the solar powerhouse of plants (chloroplasts), and addresses fundamental questions at the interface of biology and physics. The research explores chloroplasts as a manifestation of the all-pervading Second Law of Thermodynamics, advancing Australia's contribution to basic science and helping to train researchers.Read moreRead less
Oxidative stress-induced alterations of the host erythrocyte by the malaria parasite. The malaria parasite spends part of its lifecycle inside the red blood cells of its host. During this time, the parasite modifies many of the features of the red blood cell and subjects it to high levels of oxidative stress. We will use and develop a variety of fluorescence and microscopic techniques to understand the molecular basis of the alterations in the organization of membrane proteins in malaria parasit ....Oxidative stress-induced alterations of the host erythrocyte by the malaria parasite. The malaria parasite spends part of its lifecycle inside the red blood cells of its host. During this time, the parasite modifies many of the features of the red blood cell and subjects it to high levels of oxidative stress. We will use and develop a variety of fluorescence and microscopic techniques to understand the molecular basis of the alterations in the organization of membrane proteins in malaria parasite-infected red blood cells. We will examine the roles of oxidative stress and of parasite proteins in modulating the properties of the host cell membrane.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0775613
Funder
Australian Research Council
Funding Amount
$467,000.00
Summary
Automated Patch Clamp System. Ion channels are membrane proteins that underlie cell function and are therefore important drug targets. The patch clamp technique is the most powerful tool available to study the function of single ion channels. The recent automation of this technology represents a quantum leap in our ability to perform high throughput screening of novel natural and synthetic compounds as drug leads. This will lead to an urgently needed increase in capacity, increasing the volume o ....Automated Patch Clamp System. Ion channels are membrane proteins that underlie cell function and are therefore important drug targets. The patch clamp technique is the most powerful tool available to study the function of single ion channels. The recent automation of this technology represents a quantum leap in our ability to perform high throughput screening of novel natural and synthetic compounds as drug leads. This will lead to an urgently needed increase in capacity, increasing the volume of research and its outcomes, which will benefit the Australian pharmaceutical industry and biosciences research community.
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Probing membrane rafts using surface-selective multi-dimensional microscopy. The results of this project will provide fundamental insights into the role played by domains in cell membranes in the regulation of membrane protein function. These insights will create new avenues in the biotechnology industry for development of novel therapeutics aimed at disruption of membrane protein-protein interactions that cause aberant cell signalling in disease states such as cancer.
The role of mechanosensitive (MS) ion channels in magnetoreception. The magnetic field of the Earth has for long been known to influence the behaviour and orientation of a variety of organisms. Experimental study of the magnetic sense has however, been impaired by the lack of a plausible cellular and/or molecular mechanism providing meaningful explanation for detection of magnetic fields by living organisms. Recently, mechanosensitive (MS) ion channels have been implied to play a role in magneto ....The role of mechanosensitive (MS) ion channels in magnetoreception. The magnetic field of the Earth has for long been known to influence the behaviour and orientation of a variety of organisms. Experimental study of the magnetic sense has however, been impaired by the lack of a plausible cellular and/or molecular mechanism providing meaningful explanation for detection of magnetic fields by living organisms. Recently, mechanosensitive (MS) ion channels have been implied to play a role in magnetoreception. Based on our preliminary investigations, which suggest that the activity of bacterial MS channels may be affected by magnetic fields, we propose to study effects of magnetic fields on MS ion channels in Gram-negative bacteria Escherichia coli and Magnetospirillum magnetotacticum. The project promises also to contribute towards better understanding of adverse effects of electromagnetic radiation on human health and towards understanding the mechanisms behind remote magnetic-nanoparticle mediated activation of MS ion channels.Read moreRead less
Monolayer crystallization of membrane proteins. Membrane proteins comprise 25-40% of all proteins and conduct a myriad of finely tuned reactions in every cell. Despite their importance and diversity only ~40 membrane protein structures have been solved, due to the difficulty of producing high quality 2D and 3D crystals. We propose to develop and use the new monolayer crystallization technique, which employs a lipid monolayer as a crystallization template for 2D crystal production. A number of ....Monolayer crystallization of membrane proteins. Membrane proteins comprise 25-40% of all proteins and conduct a myriad of finely tuned reactions in every cell. Despite their importance and diversity only ~40 membrane protein structures have been solved, due to the difficulty of producing high quality 2D and 3D crystals. We propose to develop and use the new monolayer crystallization technique, which employs a lipid monolayer as a crystallization template for 2D crystal production. A number of important membrane proteins are available for these structural studies including ABC transporters, Caveolin-3 and the NS1 protein of Dengue virus, all of which are difficult to crystallize using conventional techniques.Read moreRead less