Ion Transport In The Malaria Parasite, Plasmodium Falciparum
Funder
National Health and Medical Research Council
Funding Amount
$225,721.00
Summary
Malaria is an infectious disease caused by single-cell protozoan parasites which, during the course of their complex lifecycle, invade the red blood cells of their human hosts. In recent years the emergence and spread of malaria parasites with high levels of antimalarial drug resistance has given rise to the very real possibility that within a few years, there will be large parts of the world in which malaria is an untreatable disease. There is therefore an urgent need for new antimalarial drugs ....Malaria is an infectious disease caused by single-cell protozoan parasites which, during the course of their complex lifecycle, invade the red blood cells of their human hosts. In recent years the emergence and spread of malaria parasites with high levels of antimalarial drug resistance has given rise to the very real possibility that within a few years, there will be large parts of the world in which malaria is an untreatable disease. There is therefore an urgent need for new antimalarial drugs. Despite the enormous clinical significance of the malaria parasite, the basic physiology of this organism is not understood. Pathways involved in ion balance, in the uptake of essential nutrients and in the release of potentially toxic waste products all play a crucial role in the survival of the parasite and are potential chemotherapeutic targets. However the properties of these pathways are, as yet, largely unknown. This work will provide fundamental (and pharmacological) information about these pathways. It will thereby open up exciting new possibilities with regard to the chemotherapy of malaria and will provide a rational basis for a strategy in which these pathways might be exploited as antimalarial drug targets.Read moreRead less
Effects Of Mutations In The Conserved Cysteine Loop Of The GABA-A Receptor
Funder
National Health and Medical Research Council
Funding Amount
$417,750.00
Summary
Inhibiting excitatory signals in the brain is the function of large proteins called GABA-A receptors. Many general anaesthetics, tranquillisers and anti-epileptic drugs act by modulating GABA-A receptors. Modern surgery would not be possible without rendering patients unconscious with general anaesthetics. However, these valuable drugs can still have unwanted side effects: for example, some of them can affect cardiac and respiratory function. There is still a need for new, more effective general ....Inhibiting excitatory signals in the brain is the function of large proteins called GABA-A receptors. Many general anaesthetics, tranquillisers and anti-epileptic drugs act by modulating GABA-A receptors. Modern surgery would not be possible without rendering patients unconscious with general anaesthetics. However, these valuable drugs can still have unwanted side effects: for example, some of them can affect cardiac and respiratory function. There is still a need for new, more effective general anaesthetics. One in every 200 people in Europe and North America suffers from epilepsy and 3% of the population suffers from anxiety. Leading, currently used general anaesthetics, anxiolytic and anti-epileptic drugs act on GABA-A receptors in the brain. The potential annual market for these drugs has been estimated to be US $2.7 billion. The world market for anaesthetics in 1999 was US $1.6 billion. All were discovered serendipitously. If the molecular site and mode of action of these drugs were understood, it is possible that new, more selective drugs could be discovered. The information gained in this project about GABA-A receptors is expected to be useful in understanding how these receptors work and in developing a new generation of drugs acting on GABA-A receptors. Specific mutations in GABA-A receptors can have a profound influence on their function. Studying the effects of mutations is slowly giving us more information about the ion channel region and drug binding sites. Recently, mutations in GABA-A receptors have been found to be associated with some forms of epilepsy. In this project, we plan to examine the effects of mutations in highly conserved residues of a small region of subunits of the GABAA receptor because: (1) we (and others) have preliminary evidence that this loop forms a connection between the GABA binding site and the ion channel and (2) we think that this part of the receptor is vital for the effects of some drugs.Read moreRead less
The general aim of this work is to investigate the three-dimensional structures of important target proteins using X-ray crystallography. Protein crystallography is the study of the three-dimensional shapes of proteins at near atomic resolution. In this method proteins are made to form crystals. X-ray beams are then shone on the crystals causing the X-rays to scatter in a pattern which is characteristic of the protein's three-dimensional shape. Knowledge of the structure of proteins is necessary ....The general aim of this work is to investigate the three-dimensional structures of important target proteins using X-ray crystallography. Protein crystallography is the study of the three-dimensional shapes of proteins at near atomic resolution. In this method proteins are made to form crystals. X-ray beams are then shone on the crystals causing the X-rays to scatter in a pattern which is characteristic of the protein's three-dimensional shape. Knowledge of the structure of proteins is necessary for the complete understanding of their biological activity and is also very useful for the rational design of new drugs that may alter their activity. Approximately one third of the body's proteins are attached to membranes. However, relatively little is known about the three-dimensional structures of this important class of proteins. In this project the structures of proteins that form pores in membrane cell walls are being determined. Some of these proteins are bacterial toxins and knowledge of their structure may prove useful in the design of new antibiotics. Another project involves work on a protein called GABA. The structure of GABA could lead to new drugs that control epilepsy, act as general anaesthetics, relieve anxiety and induce sleep.Read moreRead less
This proposal concerns the biochemical investigation of a protein called GABA receptor which is a known target for various anti-anxiety drugs (anxiolytics), anti-convulsants, sedatives, depressants, anti-epilespy drugs, alcohol and anaesthetics. This work is expected to lead to the determination of the three-dimensional shape of the protein which will provide essential information about how the protein works and lay the foundation for the design and development of new drugs to control epilepsy, ....This proposal concerns the biochemical investigation of a protein called GABA receptor which is a known target for various anti-anxiety drugs (anxiolytics), anti-convulsants, sedatives, depressants, anti-epilespy drugs, alcohol and anaesthetics. This work is expected to lead to the determination of the three-dimensional shape of the protein which will provide essential information about how the protein works and lay the foundation for the design and development of new drugs to control epilepsy, act as general anaesthetics, relieve anxiety and induce sleep.Read moreRead less
Regulation Of Voltage-Gated Potassium Channels: X-ray Structures Of Cytosolic Components Of The BK Nd Kv Families
Funder
National Health and Medical Research Council
Funding Amount
$235,500.00
Summary
This research will investigate aspects of ion channel gating (opening). Ion channels are specialised pores perforating cell membranes that facilitate transport of ions, or charged atoms, across its breadth. The flow of ions from one side to another is measurable as an electrical current. The pore, or channel, through which ions pass narrows in regions, creating an impasse, or gate , prohibiting passage. The gate is controlled by external factors, such as the binding of certain molecules (ligands ....This research will investigate aspects of ion channel gating (opening). Ion channels are specialised pores perforating cell membranes that facilitate transport of ions, or charged atoms, across its breadth. The flow of ions from one side to another is measurable as an electrical current. The pore, or channel, through which ions pass narrows in regions, creating an impasse, or gate , prohibiting passage. The gate is controlled by external factors, such as the binding of certain molecules (ligands), or, in the case of voltage-dependent ion channels, the application of a voltage to the membrane. Such perturbations widen the pore sufficiently to permit conduction. Voltage-gated potassium channels specifically transport potassium ions. They fall into multiple categories, and generally form large complexes with intracellular, as well as membrane-bound, portions. For some types, cues from intracellular chemical processes are known to regulate electrical excitability, using the intracellular domains to transfer information to the membrane. In others it is not clear if and how this might happen. Our efforts will focus on exploring this theme in two contrasting systems, Kv and BK channels. Kv channels open in response to voltage, whereas activation of BK channels requires both voltage and moderate levels of intracellular calcium. X-ray crystallography will be used to generate accurate three-dimensional images of selected potassium channel components, allowing us to visualise discrete steps in the regulation processes. Potassium channels are essential for life. They effect transmission of our nerve impulses, and are thus fundamental to central nervous system activity. This research will help us to understand the factors that control them.Read moreRead less