A5102870041- Cell death mechanisms and regulation
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Hippo pathway signaling and YAP/TAZ
- interferon and immune responses
- PARP inhibition in cancer therapy
- Catalytic C–H Functionalization Methods
- Phagocytosis and Immune Regulation
- Radical Photochemical Reactions
- Catalytic Cross-Coupling Reactions
- Chemical Synthesis and Analysis
- Oxidative Organic Chemistry Reactions
- IPv6, Mobility, Handover, Networks, Security
- Nuclear Structure and Function
- Family and Disability Support Research
- Genetics and Neurodevelopmental Disorders
- Cancer-related Molecular Pathways
- Chronic Lymphocytic Leukemia Research
- CRISPR and Genetic Engineering
- Mitochondrial Function and Pathology
- Ubiquitin and proteasome pathways
- S100 Proteins and Annexins
- Microtubule and mitosis dynamics
- NF-κB Signaling Pathways
- Barrier Structure and Function Studies
Walter and Eliza Hall Institute of Medical Research
2017-2024
The University of Melbourne
2020-2024
University of Victoria
2009-2012
Abstract Mixed lineage kinase domain-like (MLKL) is the terminal protein in pro-inflammatory necroptotic cell death program. RIPK3-mediated phosphorylation thought to initiate MLKL oligomerization, membrane translocation and disruption, although precise choreography of events incompletely understood. Here, we use single-cell imaging approaches map chronology endogenous human activation during necroptosis. During effector phase necroptosis, observe that phosphorylated assembles into higher...
The necroptosis cell death pathway has been implicated in host defense and the pathology of inflammatory diseases. While phosphorylation necroptotic effector pseudokinase Mixed Lineage Kinase Domain-Like (MLKL) by upstream protein kinase RIPK3 is a hallmark activation, precise checkpoints signaling are still unclear. Here we have developed monobodies, synthetic binding proteins, that bind N-terminal four-helix bundle (4HB) “killer” domain neighboring first brace helix human MLKL with...
Abstract The ancestral origins of the lytic cell death mode, necroptosis, lie in host defense. However, dysregulation necroptosis inflammatory diseases has led to widespread interest targeting pathway therapeutically. This mode is executed by terminal effector, MLKL pseudokinase, which licensed kill following phosphorylation its upstream regulator, RIPK3 kinase. precise molecular details underlying activation are still emerging and, intriguingly, appear mechanistically-diverge between...
Abstract The MLKL pseudokinase is the terminal effector in necroptosis cell death pathway. Phosphorylation by its upstream regulator, RIPK3, triggers MLKL’s conversion from a dormant cytoplasmic protein into oligomers that translocate to, and permeabilize, plasma membrane to kill cells. precise mechanisms underlying these processes are incompletely understood, were proposed differ between mouse human Here, we examine divergence of activation among nine vertebrate orthologues, revealing...
Necroptosis is a lytic programmed cell death pathway with origins in innate immunity that frequently dysregulated inflammatory diseases. The terminal effector of the pathway, MLKL, licensed to kill following phosphorylation its pseudokinase domain by upstream regulator, RIPK3 kinase. Phosphorylation provokes unleashing MLKL's N-terminal four-helix bundle (4HB or HeLo) domain, which binds and permeabilizes plasma membrane cause death. precise mechanism 4HB membranes, how differs between...
Abstract The necroptosis pathway is a lytic, pro-inflammatory mode of cell death that widely implicated in human disease, including renal, pulmonary, gut and skin inflammatory pathologies. precise mechanism the terminal steps pathway, where RIPK3 kinase phosphorylates triggers conformation change oligomerization effector, MLKL, are only emerging. Here, we structurally identify RIPK3-mediated phosphorylation MLKL activation loop as cue for pseudokinase domain dimerization. dimerization...
Necroptosis is a mode of programmed, lytic cell death that executed by the mixed lineage kinase domain-like (MLKL) pseudokinase following activation upstream kinases, receptor-interacting serine/threonine protein (RIPK)-1 and RIPK3. Dysregulated necroptosis has been implicated in pathophysiology many human diseases, including inflammatory degenerative conditions, infectious diseases cancers, provoking interest pharmacological targeting pathway. To identify small molecules impacting on...
Benzyl chlorides and bromides are shown to undergo copper-promoted coupling with a variety of terminal alkynes including, for the first time, electron-poor acetylenes such as methyl propiolate. The reaction permits easy access wide range (functionalized) benzyl-substituted propiolates (as well several related alkynes) from commercially available benzyl halides. These products should in turn function useful building blocks synthesis previously inaccessible heterocycles.
Application of iterative protocols to the synthesis functionally and stereochemically complex small molecules is an emerging area research with potential create new efficiencies in molecule synthesis. Similarly, discovery tandem or cascade reactions can aid rapid generation structures for biological screening programs. This report describes a cascading 6-endo-trig/5-exo-trig radical cyclization across bis-vinyl ether substrates, which are themselves iteratively synthesized from simple...
We recently described an iterative synthesis of oligo-vinyl ethers, followed by a radical cascade to provide family hexahydro-2H-furo[3,4-b]pyrans. Our results for the were consistent with either direct 6-endo-trig addition vinyl onto first ether function or initial 5-exo-trig addition, rearrangement more stable anomeric intermediate. In this report, we describe our further mechanistic studies aimed at distinguishing between these two possibilities and conclude that 5-exo/3-exo/retro-3-exo...
ABSTRACT Necroptosis is a lytic programmed cell death pathway with origins in innate immunity that frequently dysregulated inflammatory diseases. The terminal effector of the pathway, MLKL, licensed to kill following phosphorylation its pseudokinase domain by upstream regulator, RIPK3 kinase. Phosphorylation provokes unleashing MLKL’s N-terminal four-helix bundle (4HB or HeLo) domain, which binds and permeabilizes plasma membrane cause death. precise mechanism 4HB membranes, how differs...
Compounds with low-dimensional magnetic interactions can be designed by combining spin bearing metals organic molecules.The metal ions are connected e.g. to amino groups or carboxylate of the ligand and two different may bridged via molecule, thus allowing for an electron transfer between metals.Depending on size geometry molecules amount salt, many arrangements realized, e.g.dimers, trimers, chains [1] even 2dimensional sheets [2].The metal-metal distances chemical surroundings characterize...
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