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Biomolecular Structure Laboratory - Research Overview

Dr Marco G. Casarotto

One of the fascinating properties of biological molecules is their remarkable ability to trigger a range of biological responses by adopting distinct three-dimensional structures. The range of structural diversity forms the basis of a wide range of scientific disciplines ranging from molecular recognition and drug design through to protein folding and design. The Biomolecular Structure Laboratory at the JCSMR seeks to carry out research that explores how the structural properties of biological molecules can impact on biological process involved in health and disease. Through our close ties with biomedical researchers and clinicians at the JCSMR our laboratory is perfectly placed to examine how bioactivity is governed by molecular shape and recognition.

Although the main focus of our research is from a structural perspective, an integrated approach involving complementary techniques such as molecular biology, kinetics and molecular modeling are routinely employed in the laboratory. Research projects currently under investigation relate to a wide range of diseases and applications including cancer, malaria, heart disease, muscular dystrophy and virus related illnesses such as AIDS and Ross River fever.

A number of projects are currently the focus of our research efforts; these include (1) the structure, specificity and mechanism of enzyme systems and includes dihydrofolate reductase, glutathione-S-transferases and chitinases (2) structural and functional studies of muscle related proteins (3) the role of ion channels in virus associated proteins.

(1) The mechanism by which enzyme systems function is central to the development of effective therapies associated with these systems. The enzyme dihydrofolate reductase is the target for a extensive ranges of diseases such as cancer, malaria, and bacterial infections and we have used NMR structural, data, molecular biology and enzymology to determine how this enzyme functions. Enzymes, such as glutathione S-transferase, are involved in the metabolism of chemical toxins and mutagens as well as of therapeutic agents. A detailed understanding of their specificity and mechanism is crucial if one is to be able to predict the metabolism of foreign compounds.

Chitinases are sugar degrading enzymes that specifically target chitin. Both chitin and chitinase are widespread in nature, occurring in a range of organisms and are consequently, of major biotechnological interest. We are actively involved in the structural study of a chitin binding domain and chitinase with the view of investigating its binding and inhibitory properties.

(2) For skeletal and heart muscle to function properly careful regulation of calcium levels must occur. In skeletal muscle two proteins, the dihydropyridine and ryanodine receptors interact, triggering the release of calcium. We are using high resolution NMR spectroscopy to determine how these proteins function by firstly determining the structure of various regions of these proteins and then using this structural information to determine how they interact. As a result of this work we have designed a series of peptides and peptido-mimetic analogues which have the ability to regulate calcium levels in both skeletal and cardiac muscle. Such peptide therapies may hold the key to designing new drugs which be beneficial in the treatment of a range of muscle -related diseases such as heart failure, malignant hypothermia and muscular dystrophy.

(3) Many membrane proteins are essential components for the survival of viruses and we are targeting several proteins which form ion channels. The aim is to design "blockers" of the ion channels based on a structural knowledge of these ion channels. In one case, we have identified a drug which slows the replication of the AIDs virus. Work is currently underway to chemically and structurally optimise the effectiveness of this drug. This approach will give rise to a new generation of drugs to treat diseases such as HIV AIDS, hepatitis C and Ross River Fever.

Facilities

The laboratory is well equipped with access to state-of-the-art facilities including two high field Nuclear Magnetic Resonance spectrometers (Varian, Inova 500 & 600) and a network of Silicon Graphics workstations running the latest structure related software. The ANU is also due to take delivery of an 800 MHz NMR spectrometer (2004). Other facilities include stopped-flow instrumentation capable of performing CD, fluorescence and UV kinetic analysis which is housed in a well appointed molecular biology laboratory.