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.
Hierarchical modeling of protein interactions. Protein interactions play a central role in function and structural organization of cells. Their elucidation is essential for a better understanding of many cellular processes from signal transduction to enzyme inhibition. The aim of this project is to utilize the unprecedented powers of current supercomputers in developing a hierarchical model of protein interactions. The method combines Brownian dynamics at large distances and long time scales ....Hierarchical modeling of protein interactions. Protein interactions play a central role in function and structural organization of cells. Their elucidation is essential for a better understanding of many cellular processes from signal transduction to enzyme inhibition. The aim of this project is to utilize the unprecedented powers of current supercomputers in developing a hierarchical model of protein interactions. The method combines Brownian dynamics at large distances and long time scales with molecular dynamics at small distances and shorter times. Applications to both membrane proteins (blocking of ion channels by toxins and drugs) and globular proteins (ligand binding to receptors and protein association) will be considered.Read moreRead less
Structural analysis of membrane proteins using template-mediated crystallization. A new frontier technology will be developed in the form of a systematic crystallization pipeline for membrane proteins. This high throughput monolayer template technology is particularly suited for the structure determination of proteins that are otherwise difficult to crystallize and has clear commercial potential. Membrane protein structures are themselves of value to the biotechnology and pharmaceutical industry ....Structural analysis of membrane proteins using template-mediated crystallization. A new frontier technology will be developed in the form of a systematic crystallization pipeline for membrane proteins. This high throughput monolayer template technology is particularly suited for the structure determination of proteins that are otherwise difficult to crystallize and has clear commercial potential. Membrane protein structures are themselves of value to the biotechnology and pharmaceutical industry for targeted drug design, which could realise benefits in the form of novel medical treatments and reduced side effects. The monolayer template technology will also extend the capabilities of the National Cryo-EM facility, the infrastructure of which, is open for all Australian researchers. Read moreRead less
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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