A5082912631- Biochemical and Molecular Research
- Enzyme Structure and Function
- Neuroblastoma Research and Treatments
- HIV/AIDS drug development and treatment
- Pancreatic function and diabetes
- Metabolism, Diabetes, and Cancer
- Ubiquitin and proteasome pathways
- Monoclonal and Polyclonal Antibodies Research
- Enzyme Production and Characterization
- Glycosylation and Glycoproteins Research
- Research on Leishmaniasis Studies
- Cellular transport and secretion
- Cancer, Hypoxia, and Metabolism
- Trace Elements in Health
- Protein Kinase Regulation and GTPase Signaling
- RNA and protein synthesis mechanisms
- bioluminescence and chemiluminescence research
- Immune Cell Function and Interaction
- Streptococcal Infections and Treatments
- DNA Repair Mechanisms
- HER2/EGFR in Cancer Research
- Bacillus and Francisella bacterial research
- T-cell and B-cell Immunology
- Bacterial Genetics and Biotechnology
- Protein Degradation and Inhibitors
The University of Melbourne
2016-2024
St Vincents Institute of Medical Research
2010-2023
Australian Cancer Research Foundation
2017-2018
National Cheng Kung University
2011
Walter and Eliza Hall Institute of Medical Research
2005-2008
University of Oklahoma Health Sciences Center
2005
OU Health
2005
The Honourable Society of Lincoln's Inn
1996-2000
Abstract The metabolic stress-sensing enzyme AMP-activated protein kinase (AMPK) is responsible for regulating metabolism in response to energy supply and demand. Drugs that activate AMPK may be useful the treatment of diseases including type 2 diabetes. We have determined crystal structure complex with its activator 5-(5-hydroxyl-isoxazol-3-yl)-furan-2-phosphonic acid (C2), revealing two C2-binding sites γ-subunit distinct from nucleotide sites. C2 acts synergistically drug A769662...
Abstract Pore-forming proteins are weapons often used by bacterial pathogens to breach the membrane barrier of target cells. Despite their critical role in infection important structural aspects mechanism how these assemble into pores remain unknown. Streptococcus pneumoniae is world’s leading cause pneumonia, meningitis, bacteremia and otitis media. Pneumolysin (PLY) a major virulence factor S. for both small molecule drug development vaccines. PLY member cholesterol-dependent cytolysins...
Dihydrodipicolinate synthase (DHDPS) catalyzes the first committed step in lysine biosynthesis pathway of bacteria. The can be regulated by feedback inhibition DHDPS through allosteric binding end product, lysine. current dogma states that from Gram-negative bacteria are inhibited but orthologs Gram-positive species not. 1.65-Å resolution structure Legionella pneumophila and 1.88-Å Streptococcus pneumoniae bound to lysine, together with comprehensive functional analyses, show this is...
AMP-activated protein kinase (AMPK) is an αβγ heterotrimer that important in regulating energy metabolism all eukaryotes. The β-subunit exists two isoforms (β1 and β2) contains a carbohydrate-binding module (CBM) interacts with glycogen. CBM (β1- β2-CBM) are near identical sequence structure, yet show differences affinity. β2-CBM binds linear carbohydrates 4-fold greater affinity than β1-CBM single α1,6-branched up to 30-fold tighter. To understand these differences, especially for branched...
MYCN is a major driver for the childhood cancer, neuroblastoma, however, there are no inhibitors of this target. Enhanced protein stability key component oncogenesis and maintained by multiple feedforward expression loops involving transactivation target genes. Here, we reveal oncogenic role novel binding protein, proliferation-associated 2AG4 (PA2G4). Chromatin immunoprecipitation studies demonstrated that occupies PA2G4 gene promoter, stimulating transcription. Direct to blocked...
Given the rise in drug-resistant Streptococcus pneumoniae, there is an urgent need to discover new antimicrobials targeting this pathogen and equally characterize drug targets. A promising antibiotic target dihydrodipicolinate synthase (DHDPS), which catalyzes rate-limiting step lysine biosynthesis. In study, we firstly show by gene knock out studies that S. pneumoniae (sp) lacking DHDPS unable grow unless supplemented with lysine-rich media. We subsequently set structure, function stability...
Trefoil peptides are expressed near endodermal ulcerations and may modulate epithelial repair. The trefoil pancreatic spasmolytic polypeptide (PSP) was tested for growth activity in vitro on cells vivo following intragastric or intravenous infusion parenterally fed intact rats. Ion transport assessed as changes short‐circuit current rat intestine adenocarcinoma Ussing chambers. PSP stimulated of MCF‐7 Colo‐357 cells, but only the presence extracellular glutathione (GSH). effect attenuated by...
Abstract The oral pathogen Porphyromonas gingivalis is a keystone in the development of chronic periodontitis. Gingipains, principle virulence factors P. are multidomain, cell‐surface proteins containing cysteine protease domain. lysine specific gingipain, Kgp, critical factor . We have determined X‐ray crystal structure lysine‐specific domain Kgp to 1.6 Å resolution. provides insights into mechanism substrate specificity and catalysis.
The C-terminal Src kinase (Csk) and Csk-homologous (CHK) are endogenous inhibitors of the proto-oncogenic family protein tyrosine kinases (SFKs). Phosphotyrosyl peptide binding to their Src-homology 2 (SH2) domains activates Csk CHK, enhancing ability suppress SFK signalling; however, detailed mechanistic basis this activation event is unclear. CHK SH2 was expressed in Escherichia coli purified characterized as monomeric by synchrotron small-angle X-ray scattering in-line with size-exclusion...
Bioluminescence of a variety marine organisms, mostly cnidarians and ctenophores, is carried out by Ca2+-dependent photoproteins. The mechanism light emission operates via the same reaction in both animal families. Despite numerous studies on ctenophore photoprotein family, detailed catalytic arrangement amino acid residues surrounding chromophore this family are mystery. Here, we report crystal structure Cd2+-loaded apo-mnemiopsin1, member at 2.15 Å resolution used quantum...
The cholesterol-dependent cytolysins (CDCs) are the archetype for superfamily of oligomeric pore-forming proteins that includes membrane attack complex/perforin (MACPF) family immune defense and stonefish venom toxins (SNTX). CDC/MACPF/SNTX exhibits a common protein fold, which forms membrane-spanning β-barrel pore. We show changing relative stability an extensive intramolecular interface within this is necessarily disrupted to form large pore, dramatically alters kinetic...
In this paper, the crystallization and preliminary X-ray diffraction analysis to near-atomic resolution of DHDPS from Clostridium botulinum crystallized in presence its substrate pyruvate are presented. The enzyme a number forms using variety PEG precipitants, with best crystal diffracting 1.2 A belonging space group C2, contrast unbound form, which had trigonal symmetry. unit-cell parameters were = 143.4, b 54.8, c 94.3 A, beta 126.3 degrees . volume per protein weight (V(M)) was 2.3 A(3)...
In recent years, dihydrodipicolinate synthase (DHDPS; EC 4.2.1.52) has received considerable attention from both mechanistic and structural viewpoints. This enzyme, which is part of the diaminopimelate pathway leading to lysine, couples (S)-aspartate-β-semialdehyde with pyruvate via a Schiff base conserved active-site lysine. this paper, expression, purification, crystallization preliminary X-ray diffraction analysis DHDPS Clostridium botulinum, an important bacterial pathogen, are...
Human 5′‐3′ exonuclease PLD3, a member of the phospholipase D family enzymes, has been validated as therapeutic target for treating Alzheimer's disease. Here, we have determined crystal structure luminal domain enzyme at 2.3 Å resolution, revealing bilobal with catalytic site located between lobes. We then compared published structures other human PLD members which revealed that number and lipid recognition residues, previously shown to be key activity, are not conserved or, absent. This led...