Biomolecular Structure Group
Research Outline- Dr Marco 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.
