A5012971931- Alzheimer's disease research and treatments
- Prion Diseases and Protein Misfolding
- Advanced NMR Techniques and Applications
- RNA and protein synthesis mechanisms
- Ion channel regulation and function
- Cellular transport and secretion
- Parkinson's Disease Mechanisms and Treatments
- Supramolecular Self-Assembly in Materials
- Protein Structure and Dynamics
- Advanced MRI Techniques and Applications
- Lipid Membrane Structure and Behavior
- Cardiomyopathy and Myosin Studies
- Force Microscopy Techniques and Applications
- Mass Spectrometry Techniques and Applications
- Enzyme Structure and Function
- Neurological diseases and metabolism
- Cardiovascular Effects of Exercise
- interferon and immune responses
- Amino Acid Enzymes and Metabolism
- Retinal Development and Disorders
- RNA regulation and disease
- Bacterial Genetics and Biotechnology
- Platelet Disorders and Treatments
- Tea Polyphenols and Effects
- Immune Response and Inflammation
Imperial College London
2016-2022
The University of Sydney
2020
University of Minnesota
2020
Significance The misfolding and aggregation into amyloid fibrils of the prion protein (PrP) have been strongly linked with a group neurodegenerative disorders that include mad cow disease. Currently, molecular origins diseases are unknown, including underlying mechanisms PrP regions promoting its aggregation. Here, we identified structural basis by which folded domain human converts amyloids. We showed this process is promoted intermediate species forming as result pathological mutation...
Abstract The aggregation process of peptides and proteins is great relevance as it associated with a wide range highly debilitating disorders, including Alzheimer's Parkinson's diseases. natural product (‐)‐epigallocatechin‐3‐gallate (EGCG) can redirect this away from amyloid fibrils towards non‐toxic oligomers. In study we used nuclear magnetic resonance (NMR) spectroscopy to characterize the binding EGCG set natively structured unstructured proteins. results show that dramatically...
Abstract The structural dynamics governing collective motions in oligomeric membrane proteins play key roles vital biomolecular processes at cellular membranes. In this study, we present a refinement approach that combines solid-state NMR experiments and molecular simulations to accurately describe concerted conformational transitions identifying the overall structural, dynamical, topological states of proteins. accuracy ensembles generated with method is shown reach statistical error limit,...
Membrane binding by α-synuclein (αS), an intrinsically disordered protein whose aggregation is associated with Parkinson’s disease, a key step in determining its biological properties under both physiological and pathological conditions. Upon membrane interaction, αS retains partial level of structural disorder despite acquiring α-helical content. In the membrane-bound state, equilibrium between helical-bound disordered-detached states central region (residues 65–97) has been involved...
The chemical shifts measured in solution-state and solid-state nuclear magnetic resonance (NMR) are powerful probes of the structure dynamics protein molecules. exploitation requires methods to correlate these data with structures sequences. We present here an approach calculate accurate both ordered disordered proteins using exclusively information contained their Our sequence-based approach, sequences shift correlations (PROSECCO), achieves accuracy most advanced structure-based...
DNA mimicry by proteins is a strategy that employed some to occupy the binding sites of DNA-binding and deny further access these DNA. Such have been found in bacteriophage, eukaryotic virus, prokaryotic, cells imitate non-coding functions Here, we report another phage protein Gp44 from bacteriophage SPO1 Bacillus subtilis , employing as part unusual inhibit host RNA polymerase. Consisting three simple domains, contains motif, flexible mimic domain random-coiled domain. able anchor genome...
The interferon-induced transmembrane (IFITM) protein family comprises a class of restriction factors widely characterised in humans for their potent antiviral activity. Their biological activity is well documented several animal species, but genetic variation and mechanism less understood, particularly avian species. Here we report the complete sequence domestic chicken Gallus gallus IFITM locus from wide variety breeds to examine detailed pattern on chromosome 5, including flanking genes...
The membrane binding by α-synuclein (αS), a presynaptic protein whose aggregation is strongly linked with Parkinson's disease, influences its biological behavior under functional and pathological conditions. This interaction requires conformational transition from disordered-unbound to partially helical membrane-bound state of the protein. In present study, we used enhanced coarse-grained MD simulations characterize sequence determinants synaptic-like vesicles N-terminal region αS. anchor...
A novel Rab27A construct enables elucidation of covalent ligand binding, paving the way for structure-guided approaches against this challenging target.
Some recent advances in biomolecular simulation and global optimization have used hybrid restraint potentials, where harmonic restraints that penalize conformations inconsistent with experimental data are combined molecular mechanics force fields. These potentials can be to improve the performance of dynamics, structure prediction, energy landscape sampling, other computational methods rely on accuracy underlying field. Here, we develop a potential based NapShift, an artificial neural...
BackgroundVon Willebrand factor (VWF) contains a number of free thiols, the majority which are located in its C‐domains, and these have been shown to alter VWF function, However, impact thiols on function following acute exposure collagen under high pathological shear stress has not determined.MethodsVWF were blocked with N‐ethylmaleimide flow assays performed rates determine platelet capture binding function. Atomic force microscopy (AFM) was used probe interaction molecular simulations...
Alzheimer's disease is imposing a growing social and economic burden worldwide, effective therapies are urgently required. One possible approach to modulation of the outcome use small molecules limit conversion monomeric amyloid (Aβ42) cytotoxic oligomers fibrils. We have synthesized modulators assembly that unlike others studied date: these compounds act primarily by sequestering Aβ42 monomer. provide kinetic nuclear magnetic resonance data showing perphenazine conjugates divert monomer...
Phospholamban (PLN) is a mini-membrane protein that directly controls the cardiac Ca 2+ -transport response to β-adrenergic stimulation, thus modulating output during fight- or-flight response. In sarcoplasmic reticulum membrane, PLN binds sarco(endo)plasmic -ATPase (SERCA), keeping this enzyme’s function within narrow physiological window. phosphorylation by cAMP-dependent kinase A or increase in concentration reverses inhibitory effects through an unknown mechanism. Using oriented-sample...
Transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative disorders associated with the misfolding and aggregation of human prion protein (huPrP). Despite efforts into investigating process huPrP aggregation, mechanisms triggering its remain elusive. A number TSE-associated mutations have been identified, but their role at onset progression diseases is unclear. Here we report NMR assignments C-terminal globular domain wild type pathological mutant T183A. The differences in...
Abstract Alzheimer’s disease is imposing a growing social and economic burden worldwide effective therapies are required. Strategies aimed at the removal of fibrillar plaques formed by amyloid-β peptide have not proved therapeutic focus has shifted to approaches that target cytotoxic oligomeric species populated before fibrils deposited. We designed synthesized perphenazine-cyclam conjugates specifically rapidly bind monomeric form Aβ42, reducing production both oligomers amyloid fibrils....