A. Designing novel insulins
Diabetes is a significant contributor to the global burden of disease. The current treatment for Type-1 diabetes (T1D) and late-stage Type-2 diabetes (T2D) is the subcutaneous injection of insulin. Worldwide, more than 200 million individuals require daily insulin injections. Despite this life-saving treatment, many patients will suffer from diabetes-related illnesses, including cardiovascular and kidney disease. There is an urgent need to develop new forms of insulin that are faster acting and are more stable, obviating the need for cold storage. This work focuses on using computational tools, primarily molecular dynamics (MD), to investigate the interaction of insulin with its cognate receptor, the insulin receptor (IR).
B. Differentiation of ligand response in the mineralocorticoid receptor
The mineralocorticoid receptor (MR) plays a vital role in critical physiological progress such as water-electrolyte homeostasis and blood pressure regulation. In collaboration with Prof Peter Fuller from the Hudson Institute of Medical Research, we investigate how receptors from different species respond differently to the same ligand. Recently, we identified a single-point mutation in the MR that converts an agonist ligand to an antagonist. In another species, the same ligand converts from an antagonist into an agonist. From an understanding of ligand diorism, it should be possible to design new therapeutics against the nuclear receptor family proteins with a specific function.
C. Exploring the mechanism of gating in the potassium channel KirBac3.1
Ion channels mediate ionic diffusion across cell membranes. Orchestrated ion channel activity propagates the electrical signals that drive the human central nervous system and vital organs and underpins neurological, cardiac, endocrine, and essential developmental and homeostatic functions. Potassium channels, of which the human genome encodes over eighty, fine-tune the membrane potential, participate in cascades that regulate local Ca2+ levels, facilitate cellular messaging, and are responsible for adjusting cell volume required to commit to cell cycle progression. Thus, their actions are directly or indirectly intrinsic to the signal transduction pathways that control cell division and apoptosis, activation of immune cells, and regulation of cell function. Naturally occurring mutations impairing the ability to gate K+ currents are linked to a broad spectrum of diseases (including heart arrhythmia, diabetes, and others), and recent investigations have decisively linked anomalous expression of native K+ channels in cancer cells to invasiveness and malignancy of brain, colon and breast cancers. In collaboration with Dr. Jacqui Gulbis, WEHI, aims to uncover the mechanism of gating and conduction in one of these channels, KirBac3.1.
D. Simulating the passage of peptides across membranes
Bim is a key protein that triggers the process of programmed cell death, apoptosis. Small peptides from a small region of this protein, the BH3 domain, with a hydrocarbon linkage have been shown to efficiently penetrate the cell membrane, whereas the native peptide does not. In this project, we have been exploring the mechanism of BimBH3 peptide membrane penetration.
~ Professor Brian Smith