A5040684603- Advanced Materials Characterization Techniques
- Machine Learning in Materials Science
- Electron and X-Ray Spectroscopy Techniques
- X-ray Diffraction in Crystallography
- HIV/AIDS drug development and treatment
- Protein Structure and Dynamics
- Peroxisome Proliferator-Activated Receptors
- Chemical Synthesis and Analysis
- Bacterial Genetics and Biotechnology
- Antibiotic Resistance in Bacteria
- Enzyme Structure and Function
- Click Chemistry and Applications
- HIV Research and Treatment
- Monoclonal and Polyclonal Antibodies Research
- RNA and protein synthesis mechanisms
- Biochemical and Structural Characterization
- Protein Degradation and Inhibitors
- Computational Drug Discovery Methods
- Drug Transport and Resistance Mechanisms
- Synthesis and characterization of novel inorganic/organometallic compounds
- Glycosylation and Glycoproteins Research
- Organometallic Compounds Synthesis and Characterization
- Peptidase Inhibition and Analysis
- Mitochondrial Function and Pathology
- Biochemical and Molecular Research
Monash University
2016-2025
Australian Regenerative Medicine Institute
2013-2025
The University of Sydney
2024
Institute of Medicinal Plant Development
2001-2019
Johns Hopkins University
2016
The University of Texas System
2015
Anderson Hospital
2015
ARC Centre of Excellence for Coherent X-ray Science
2012-2014
The University of Queensland
1995-2014
Australian Research Council
2013-2014
Significance The four-helix bundle (4HB) domain of Mixed Lineage Kinase Domain-Like (MLKL) bears two clusters residues that are required for cell death by necroptosis. Mutations within a cluster centered on the α4 helix 4HB MLKL prevented its membrane translocation, oligomerization, and ability to induce This is composed principally acidic therefore challenges idea engages negatively charged phospholipid membranes via conventional positively interaction surface. importance translocation...
Therapeutic targeting of the neurokinin 1 receptor in endosomes provides efficacious and prolonged pain relief.
A large number of macrocyclic miniproteins with diverse biological activities have been isolated from the Rubiaceae, Violaceae, and Cucurbitaceae plant families in recent years. Here we report three-dimensional structure determined using 1H NMR spectroscopy demonstrate potent insecticidal activity for one these peptides, kalata B2. This peptide is major components an extract leaves Oldenlandia affinis. The consists a distorted triple-stranded β-sheet cystine knot arrangement disulfide bonds...
The brain has a limited ability to synthesize the essential polyunsaturated fatty acid (PUFA) docosahexaenoic (DHA) from its omega-3 precursors. Therefore, maintain concentrations of this PUFA at physiological levels, plasma-derived DHA must be transported across blood-brain barrier (BBB). While is able partition into luminal membrane endothelial cells, low aqueous solubility likely limits cytosolic transfer abluminal membrane, necessitating requirement an intracellular carrier protein...
The low-density lipoprotein (LDL) receptor plays a central role in mammalian cholesterol metabolism, clearing lipoproteins which bear apolipoproteins E and B-100 from plasma. Mutations this molecule are associated with familial hypercholesterolemia, condition leads to an elevated plasma concentration accelerated atherosclerosis. N-terminal segment of the LDL contains heptad cysteine-rich repeats that bind lipoproteins. Similar present related receptors, including very receptor-related...
Inhibitors of proteolytic enzymes (proteases) are emerging as prospective treatments for diseases such AIDS and viral infections, cancers, inflammatory disorders, Alzheimer's disease. Generic approaches to the design protease inhibitors limited by unpredictability interactions between, structural changes to, inhibitor during binding. A computer analysis superimposed crystal structures 266 small molecule bound 48 proteases (16 aspartic, 17 serine, 8 cysteine, 7 metallo) provides first...
The cysteine-rich secretory proteins (Crisp) are predominantly found in the mammalian male reproductive tract as well venom of reptiles. Crisps two domain with a structurally similar yet evolutionary diverse N-terminal and characteristic C-terminal domain, which we refer to Crisp domain. We presented NMR solution structure mouse Tpx-1, showed that it contains subdomains, one has fold ion channel regulators BgK ShK. Furthermore, have demonstrated for first time regulatory activity is...
We have identified a class of molecules, known as 2-aminothiazoles (2-ATs), frequent-hitting fragments in biophysical binding assays. This was exemplified by 4-phenylthiazol-2-amine being hit 14/14 screens against diverse range protein targets, suggesting that this scaffold is poor starting point for fragment-based drug discovery. prompted us to analyze the context an academic fragment library used discovery (FBDD) and two larger compound libraries high-throughput screening (HTS). analysis...
Fatty acid-binding protein 5 (FABP5) at the blood–brain barrier contributes to brain uptake of docosahexaenoic acid (DHA), a blood-derived polyunsaturated fatty essential for maintenance cognitive function. Given importance DHA in cognition, aim this study was investigate whether deletion FABP5 results dysfunction and is associated with reduced endothelial cell exogenous subsequent attenuation levels endogenous DHA. Cognitive function assessed male female +/+ −/− mice using battery memory...
Small heat-shock proteins (sHsps) are molecular chaperones that play an important protective role against cellular protein misfolding by interacting with partially unfolded on their off-folding pathway, preventing aggregation. Polyglutamine (polyQ) repeat expansion leads to the formation of fibrillar aggregates and neuronal cell death in nine diseases, including Huntington disease spinocerebellar ataxias (SCAs). There is evidence sHsps have a suppression polyQ-induced neurodegeneration; for...
Fragment screening is becoming widely accepted as a technique to identify hit compounds for the development of novel lead compounds. In neighboring laboratories, we have recently, and independently, performed fragment campaign on HIV-1 integrase core domain (IN) using similar commercially purchased libraries. The two campaigns used different methods preliminary identification hits; one saturation transfer difference nuclear magnetic resonance spectroscopy (STD-NMR), other surface plasmon...
Nuclear hormone receptors (NHRs) regulate the expression of proteins that control aspects reproduction, development and metabolism, are major therapeutic targets. However, NHRs ubiquitous participate in multiple physiological processes. Drugs act at therefore commonly restricted by toxicity, often nontarget organs. For endogenous NHR ligands, intracellular lipid-binding proteins, including fatty acid-binding (FABPs), can chaperone ligands to nucleus promote activation. also bind FABPs,...
Abstract The thiol‐disulfide oxidoreductase enzyme DsbA catalyzes the formation of disulfide bonds in periplasm Gram‐negative bacteria. substrates include proteins involved bacterial virulence. In absence DsbA, many these do not fold correctly, which renders bacteria avirulent. Thus is a critical mediator virulence and inhibitors may act as antivirulence agents. Biophysical screening has been employed to identify fragments that bind from Escherichia coli . Elaboration one produced compounds...
Small molecules that covalently modify proteins typically contain an electrophile selectively reacts with nucleophilic residues in a protein target, such as cysteine, serine, and threonine. Targeting other amino acids is emerging strategy covalent probe design. This study reports the discovery characterization of reaction between novel allene warhead histidine residue active site bacterial thiol–disulfide oxidoreductase enzyme Escherichia coli DsbA (EcDsbA). Allenes have not been widely...
Disulfide bond protein A (DsbA) plays a pivotal role in catalysing the formation of disulfide bonds within periplasm most Gram-negative bacteria. As this process is required for folding multiple virulence-associated proteins, inhibitors DsbA have potential to be developed as novel anti-virulence agents. Despite extensive efforts develop high-affinity targeting canonical substrate-binding site, success has been limited. In current work, we describe dynamics-driven fragment discovery approach....
Cyclic tetrapeptides are an intriguing class of natural products. To synthesize highly strained cyclic we developed a macrocyclization strategy that involves the inclusion 2-hydroxy-6-nitrobenzyl (HnB) group at N-terminus and in "middle" sequence. The N-terminal auxiliary performs ring closure/ring contraction role, backbone promotes cis amide bonds to facilitate otherwise difficult contraction. Following this route, all-l tetrapeptide cyclo-[Tyr-Arg-Phe-Ala] was successfully prepared.
Liver-fatty acid binding protein (L-FABP) is found in high levels enterocytes and involved the cytosolic solubilization of fatty acids during fat absorption. In current studies, interaction L-FABP with a range lipophilic drugs has been evaluated to explore potential for provide an analogous function absorption drugs. Binding affinity was assessed by displacement fluorescent marker, 1-anilinonaphthalene-8-sulfonic (ANS), site location determined via nuclear magnetic resonance chemical shift...
Oxidative protein folding in Gram-negative bacteria results the formation of disulfide bonds between pairs cysteine residues. This is a multistep process which dithiol-disulfide oxidoreductase enzyme, DsbA, plays central role. The structure DsbA comprises an all helical domain unknown function and thioredoxin domain, where active site cysteines shuttle oxidized, substrate-bound, reduced form DsbB-bound form, DsbB membrane that reoxidizes DsbA. Most enzymes interact with wide variety...
The decoration of the lipid A headgroups lipooligosaccharide (LOS) by LOS phosphoethanolamine (PEA) transferase (LptA) in Neisseria spp. is central for resistance to polymyxin. structure globular domain LptA shows that protein has five disulphide bonds, indicating it a potential substrate oxidation pathway bacterial periplasm. When neisserial was expressed Escherichia coli presence oxidoreductase, EcDsbA, polymyxin increased 30-fold. decorated one position E. with PEA. In absence degraded...
Abstract The biogenesis of membranes from constituent proteins and lipids is a fundamental aspect cell biology. In the case assembled into bacterial outer membranes, an overarching question concerns how energy required for protein insertion folding accessed at this remote location cell. translocation assembly module (TAM) nanomachine that functions in membrane virulence diverse pathogens. Here we demonstrate interactions through which TamA TamB subunits dock to bridge periplasm unite aspects...