The Structural Basis Of Cytokine Signalling Inhibition
Funder
National Health and Medical Research Council
Funding Amount
$239,473.00
Summary
Cell-cell communcation is vital for the correct functioning of the body. Cells need to be told the correct time to divide, to produce certain enzymes or chemicals, to migrate and also when to apoptose, or die. Cells receive these signals through the binding of small soluble proteins called cytokines. Cytokines bind to specialized receptors on the surface of the cell and initiate an intracellular signaling cascade that passes the correct message to the nucleus. It is important that cells react to ....Cell-cell communcation is vital for the correct functioning of the body. Cells need to be told the correct time to divide, to produce certain enzymes or chemicals, to migrate and also when to apoptose, or die. Cells receive these signals through the binding of small soluble proteins called cytokines. Cytokines bind to specialized receptors on the surface of the cell and initiate an intracellular signaling cascade that passes the correct message to the nucleus. It is important that cells react to these protein messengers however it is just as vital that they don't overreact. Many human diseases, especially inflammatory diseases such as rheumatoid arthritis and type II diabetes, are due to aberrant cytokine signaling. To ensure this doesn't occur, cells have evolved a mechanism to quickly switch off the signaling cascade after it has started. This mechanism involves an entire family of proteins, the Suppressors of Cytokine Signalling (SOCS) family. These proteins can act via two distinct mechanisms. The first is to directly block the JAK-STAT proteins, proteins that initiate the intracellular part of the signaling cascade. The second mechanism has been less well studied, it involves the SOCS proteins upregulating the degradation of signaling intermediates. The SOCS proteins can do this through the action of a 40 residue domain called the SOCS box. The SOCS box directs proteins bound to other domains of the SOCS proteins to be degraded by interacting with a complex called an E3 ubiquitin ligase. This project involves determining the three-dimensional atomic structure of the SOCS-E3 ligase interaction and investigating biophysical aspects of the interaction. This information will lead to a fuller understanding of the mechanism of signaling inhibition and will provide information crucial to the design of SOCS inhibitors. Such inhibitors would be therapeutically important in the treatment of a number of human diseases such as cancer, arthritis and type II diabetes.Read moreRead less
Structural Studies Of The Jak And Abl Kinases: A Prerequisite For Drug Design
Funder
National Health and Medical Research Council
Funding Amount
$360,965.00
Summary
Protein tyrosine kinases (PTK) are a large, pivotal family of signalling molecules implicated in diseases such as cancer and immune related disorders. This fellowship aims to develop more potent kinase inhibitors of a number of PTKs using Cytopia’s drug discovery capability coupled with the X-ray crystallography expertise within Monash University. This innovative approach will permit a rational structure-based drug discovery platform to be established and will lead to the creation of a portfolio ....Protein tyrosine kinases (PTK) are a large, pivotal family of signalling molecules implicated in diseases such as cancer and immune related disorders. This fellowship aims to develop more potent kinase inhibitors of a number of PTKs using Cytopia’s drug discovery capability coupled with the X-ray crystallography expertise within Monash University. This innovative approach will permit a rational structure-based drug discovery platform to be established and will lead to the creation of a portfolio of phase I therapeutics, which will be of substantial benefit in the medical health area.Read moreRead less
Recent evidence suggests that the Siah proteins are involved in sensing low oxygen levels in cells, and subsequently activating processes to help the cell survive under these conditions. Low oxygen conditions occur in cancer and sites of inflammation, suggesting that inhibiting Siah may improve patient outcomes in diseases such as cancer and arthritis. We aim to perform a high throughput screen for drugs that inhibit Siah protein function and to test these in cancer cells.
Structural Characterisation Of SNARE Protein Complexes Involved In Insulin-regulated Glucose Transport
Funder
National Health and Medical Research Council
Funding Amount
$320,803.00
Summary
Insulin-regulated glucose transportation is defective in type 2 diabetes, a disease that is a major health problem worldwide and in some cases can lead to death. The aim of this work is to investigate the molecular structure and function of proteins critical to the transportation and delivery of glucose to muscle and fat cells, which will lead to the validation of new therapeutic targets and the development of new treatments for diabetes.
SPRY Domain-containing SOCS Box (SSB) Protein Interaction With Par-4: Structure And Biochemical Implications
Funder
National Health and Medical Research Council
Funding Amount
$529,565.00
Summary
The suppressor of cytokine signalling (SOCS) proteins, are intracellular molecules that negatively regulate hormone and growth factor action, and whose functional importance has been borne out in many physiological studies. The SOCS box is a small part of the SOCS proteins that is believed to facilitate degradation of SOCS target proteins. The SPRY domain-containing SOCS box protein-2 (SSB-2) is one of four proteins within the greater SOCS family (SSB-1 to -4), which have a SOCS box and a centra ....The suppressor of cytokine signalling (SOCS) proteins, are intracellular molecules that negatively regulate hormone and growth factor action, and whose functional importance has been borne out in many physiological studies. The SOCS box is a small part of the SOCS proteins that is believed to facilitate degradation of SOCS target proteins. The SPRY domain-containing SOCS box protein-2 (SSB-2) is one of four proteins within the greater SOCS family (SSB-1 to -4), which have a SOCS box and a central SPRY domain. The SPRY domain mediates interaction with other proteins within the cell. Over 300 proteins are known to contain a SPRY domain. We recently determined the first atomic structure of a SPRY domain as part of SSB-2, using nuclear magnetic resonance (NMR) spectroscopy. We further identified Par-4 (prostate apoptosis response-4) as a novel and direct protein binding partner for SSB-1, -2 and -4, but not SSB-3. Extensive mutational analysis subsequently identified a series of SSB-2 mutants that were unable to bind Par-4 but retained structural integrity. Cancer cells develop through a series of genetic events and escape programmed cell death or apoptosis, continuing to grow inappropriately. Par-4 was originally discovered as a gene up-regulated in prostate cancer cells undergoing apoptosis and primarily appears to sensitise cancer cells to apoptotic stimuli. This proposal aims to further investigate SSB-Par-4 binding. The 3D structure of the complex will be determined and biochemical consequences of this interaction characterised. If SSB proteins regulate Par-4 levels, then chemical disruption of SSB-Par-4 binding could potentially result in an increase in Par-4 protein levels, making cancer cells more susceptible to killing by cytotoxic drugs.Read moreRead less
Translocase Of The Outer Mitochondrial Membrane: X-ray Structure Determination Of Core Components
Funder
National Health and Medical Research Council
Funding Amount
$336,118.00
Summary
This research will address the issue of protein transport into mitochondria, cellular organelles bounded by a complex double-membrane system that are primarily responsible for servicing the energy requirements of actively respiring cells. The outer membrane, or envelope, surrounding each mitrochondrion, is separated from a second (or inner) membrane by an inter-membrane space. The translocase of the outer mitochondrial membrane (TOM) cooperates with the translocase of the inner mitochondrial mem ....This research will address the issue of protein transport into mitochondria, cellular organelles bounded by a complex double-membrane system that are primarily responsible for servicing the energy requirements of actively respiring cells. The outer membrane, or envelope, surrounding each mitrochondrion, is separated from a second (or inner) membrane by an inter-membrane space. The translocase of the outer mitochondrial membrane (TOM) cooperates with the translocase of the inner mitochondrial membrane (TIM) to mediate the passage of unfolded preproteins into the mitochondria. Proteins are usually bulky in their active folded state, so preproteins transit the membrane as extended polypeptide chains, as the channel through which they pass is relatively narrow. Ancillary praoteins aid in recognition and targeting of preproteins, and help to maintain them in an unfolded state prior to their translocation through the pore, and later ensure that they are able to fold into the correct conformation once they have arrived in the mitochondria. Our research will entail determination of the three-dimensional atomic-level structures of selected constituents of the TOM machinery, allowing us to visualise freeze-frame snapshots of some aspects of protein translocation in molecular details. In combination with recent biochemical data, this information will provide an architectural framework which we can use to help in our interpretation of complicated structure-function relationships between components of TOM and other proteins with which they integrate their activities during translocation events. Ultimately such fundamental research will lead to the development of strategies for dealing with disorders linked to mitochondrial defects in humans, including, amongst others, Parkinson's and Alzheimer's diseases.Read moreRead less
Structure, Transport And Assembly Of PorB, A Key Invasion Molecule Of Meningococcal Disease
Funder
National Health and Medical Research Council
Funding Amount
$292,639.00
Summary
When the bacteria that cause meningococcal disease invade cells, they use specialized cell surface pore proteins to hijack the human cell and maintain infection. This research will study the structure of these bacterial pore proteins to help understand how they function to subvert normal cellular processes, and this insight will be important in the development of new treatments for meningococcal disease.
Role Of Conformational Change In Activation Of The Growth Hormone Receptor
Funder
National Health and Medical Research Council
Funding Amount
$242,545.00
Summary
Growth hormone is an important hormone therapeutic for treating dwarfism. Recently, many new therapeutic applications for growth hormone have been discovered, particularly in relation to its role as an anabolic agent. These include post surgery recovery, enhanced bone fracture healing, Crohns disease, dilated cardiomyopathy, infertility and of course, ageing. This project seeks to find out how growth hormone sends its signal into the target cell through its surface receptor. It is believed that ....Growth hormone is an important hormone therapeutic for treating dwarfism. Recently, many new therapeutic applications for growth hormone have been discovered, particularly in relation to its role as an anabolic agent. These include post surgery recovery, enhanced bone fracture healing, Crohns disease, dilated cardiomyopathy, infertility and of course, ageing. This project seeks to find out how growth hormone sends its signal into the target cell through its surface receptor. It is believed that the primary event in signalling is the ability of the hormone to bring two receptors together (receptor dimerization). However, it may be that the receptor already is dimerized, and the role of the hormone is to induce a specific change in shape of the receptor, which transfers the signal of hormone binding into the cell to initiate signalling to the genome. We have good evidence that a specific shape change is required for activation of an important signalling pathway by growth hormone, and the closely structurally related receptor for erythropoietin is already dimerized before hormone binds. We want to find out exactly how the shape change acts, and whether the receptor is predimerized. This information is vital for designing small orally active mimics of growth hormone which could be of great value as an anabolic supplement for the frail elderly.Read moreRead less
Plant immunity to fungal and bacterial pathogens. Since 2003, the Australian wheat crop has been threatened by a continuing stripe rust epidemic, which has required an additional production expense of at least $100 million per annum in fungicides. This Australian National University (ANU) - Commonwealth Scientific and Industrial Research Organisation (CSIRO) joint proposal aims to exploit the next-generation genome sequencing and associated bioinformatic and proteomic methods which are poised to ....Plant immunity to fungal and bacterial pathogens. Since 2003, the Australian wheat crop has been threatened by a continuing stripe rust epidemic, which has required an additional production expense of at least $100 million per annum in fungicides. This Australian National University (ANU) - Commonwealth Scientific and Industrial Research Organisation (CSIRO) joint proposal aims to exploit the next-generation genome sequencing and associated bioinformatic and proteomic methods which are poised to revolutionise biology to investigate the wheat-fungus interaction. We will develop new effective approaches for environmentally benign stripe rust control based on new knowledge about how this fungus causes disease and avoids the wheat's immune surveillance system.Read moreRead less