Structural Biology - Research Units - Structural Biology - Research themes
Structural biology of cancer incorporating the ACRF Rational Drug Discovery Facility
The work undertaken by SVI scientists has provided major contributions to identification of targets for cancer therapy, and understanding the mechanisms of cancer growth and spread. This work was recognised in 2005 by a generous grant from the Australian Cancer Research Foundation to help establish the ACRF Rational Drug Discovery Facility at the Institute. SVI is a founding member of the Cooperative Research Centre for Cancer Therapeutics which aims to translate basic cancer discoveries into the clinic. BSBL is the core structural biology unit for the CRC. Examples of the cancer projects currently being pursued by BSBL include:
GM-CSF receptor (with Prof Angel Lopez and Dr Tim Hercus, Centre for Cancer Biology, Adelaide)
Cytokine receptors are transmembrane cell surface glycoproteins that bind specifically to cytokines and transduce their signals which can direct cells to proliferate, differentiate or even die. The GM-CSF, IL-3 and IL-5 family of cytokines regulates the survival, proliferation, differentiation and functional activation of hematopoietic cells. These same cytokines have also been implicated in multiple pathologies resulting from the excessive or aberrant expression of the cytokine or their receptors, in conditions such as certain types of leukaemia. We recently determined the structure of a GM-CSF:receptor ternary complex, representing the first structure of an "activated" receptor of this family of cytokines. Inspection of the structure revealed exciting insights into the mechanism of receptor activation and provided a unifying molecular explanation for the diverse functional properties of related cytokine:receptor systems. To maximise the drug development opportunities of this discovery we have formed a partnership with the biopharmaceutical company CSL Limited to discover and develop therapeutic antibodies that will disrupt aberrant signalling by the receptor.
Glutathione transferases (with Prof Mario Lo Bello, University of Rome, Italy; Prof Paul Dyson, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland; Prof Philip Board, Australian National University, Canberra; Dr Luis García-Fuentes, University of Almería, Spain)
Glutathione S-transferases (GSTs) are a supergene family of enzymes that play a pivotal role in the detoxification of foreign chemicals and toxic metabolites. Paradoxically, the detoxifying activity of these enzymes is in part responsible for the development of cellular multi-drug resistance towards a number of chemotherapeutic agents. We have determined more than 50 GST crystal structures which have contributed to an understanding of the molecular basis of substrate recognition and catalysis by the enzyme superfamily. Inhibitors of GSTs have been used in clinical trials as adjuvants in cancer chemotherapy with some success. However, the use of these inhibitors has produced undesirable side effects and more suitable inhibitors are urgently being sought.
Structural neurobiology
Mental illness encompasses a multitude of devastating conditions that present a major burden to the Australian economy. These conditions are often chronic and debilitating, posing the highest health, economic and social capital attrition burden to Australia of any disease group. BSBL are pursuing a number of projects with aim of understanding how key proteins function in the brain with the ultimate aim of discovering new drugs to treat mental illness. Examples include:
Amyloid Precursor Protein (with Prof Colin Masters, Mental Health Research Institute and A/Prof Kevin Barnham, Melbourne University)
Alzheimer's disease is the most prevalent neuro-degenerative disease in humans and is the fourth leading cause of death in the developed world. The disease is characterized by the presence of amyloid plaques that principally derive from amyloid precursor protein (APP). The long term aim of this project is to determine the complete structure of APP in order to understand its normal physiological function and as a basis for structure-based drug design of anti-Alzheimer's drugs. We are solving the structure of APP by a divide-and-conquer approach: solving the structures of small, overlapping fragments with the eventual aim of piecing the molecule together. To date we have determined the structures of three regions of APP: the growth factor domain, the copper-binding domain and the Abeta peptide bound to a range of antibodies.
IRAP (with Dr Siew Yeen Chai, Monash University)
Central administration of the hexapeptide angiotensin IV markedly enhances memory and learning in rodents. This effect is mediated by binding to a specific, high-affinity site in the brain which our collaborators identified to be the transmembrane enzyme, insulin-regulated aminopeptidase (IRAP). The peptide binds with high affinity to the catalytic domain of IRAP inhibiting its enzymatic activity. Using a molecular model of the catalytic domain, we have screened compound databases and have identified compounds that inhibit IRAP and reverse memory deficits in animals. To date, there is no proven effective treatment for cognitive impairment. Since the causes of cognitive impairment range from birth defects (Down's syndrome, mental retardation, cerebral palsy), recreational drug abuse, opportunistic infections to neurological conditions (stroke, brain trauma, neurodegeneration such as Alzheimer's disease), prevention therapies are not effective alternatives. The IRAP inhibitors may lead to the development of new classes of cognitive enhancers.
Structural biology of infection
BSBL have made major contributions to our understanding of how bacterial pore-forming toxins can pass through the walls of target cells. In recent years this work has expanded into studies of other infectious organisms such as parasites and viruses. Some examples of our work include:
Protein toxins (with Prof Rod Tweten, University of Oklahoma, USA; Dr Adam Ratner, Columbia University, USA)
Pore-forming toxins are promising model systems for understanding the biogenesis, structure and function of membrane channels as well as being potential targets for new antibiotics. One example of our work is perfringolysin O (PFO), a 52 kDa toxin secreted by the gas gangrene bacterium Clostridium perfringens, a member of a family of more than 20 toxins produced by Gram-positive bacteria. This family is often referred to as cholesterol-dependent cytolysins (CDCs) because of their strict requirement for membrane-bound cholesterol for activity. The presumed common mode of action of these toxins involves binding to target cell membranes via cholesterol, insertion into the lipid bilayer of target cells followed by oligomerisation and pore formation leading to cytolysis. However, the details of the molecular mechanism of membrane damage are not known. We have now determined the crystal structures of a number of CDCs. Current work revolves around understanding how CDC toxins penetrate membranes.
Commercial projects (with Biota Holdings, Melbourne)
Biota Holdings is a publicly listed company, established in 1985 for the express purpose of funding human pharmaceutical discovery and development. In 1998 Biota saw its first products commercialised internationally. The company's influenza drug, Relenza, was the first new drug for the treatment of flu in more than 30 years and their diagnostic kit, FLU OIA, was the first rapid point-of-care diagnostic for detecting influenza A and B. It is Biota's vision to become a dominant player in the global viral respiratory diseases arena. Biota uses structure-based drug design as a technology platform for developing respiratory disease drugs as well as drugs directed towards other viral diseases.