A5090535546- Carbohydrate Chemistry and Synthesis
- Glycosylation and Glycoproteins Research
- Lysosomal Storage Disorders Research
- Enzyme Structure and Function
- Enzyme Production and Characterization
- Trypanosoma species research and implications
- Enzyme Catalysis and Immobilization
- Biochemical Acid Research Studies
- Biochemical and Molecular Research
- Synthesis and Catalytic Reactions
- Biofuel production and bioconversion
- Diet, Metabolism, and Disease
- Protein Tyrosine Phosphatases
- Natural Antidiabetic Agents Studies
- Microtubule and mitosis dynamics
- Enzyme function and inhibition
- Cassava research and cyanide
- Pancreatic function and diabetes
- Ubiquitin and proteasome pathways
- Studies on Chitinases and Chitosanases
- Alkaline Phosphatase Research Studies
- Microbial metabolism and enzyme function
- Click Chemistry and Applications
- Cancer-related Molecular Pathways
- Crystallization and Solubility Studies
University of York
2019-2024
Newcastle University
2023-2024
University of Virginia
2020
New York Structural Biology Center
2019
Plant polysaccharides represent a virtually unlimited feedstock for the generation of biofuels and other commodities. However, extraordinary recalcitrance plant toward breakdown necessitates continued search enzymes that degrade these materials efficiently under defined conditions. Activity-based protein profiling provides route functional discovery such in complex mixtures industrially relevant Here, we show detection identification β-xylosidases endo-β-1,4-xylanases secretomes Aspergillus...
Gaucher disease is caused by inherited deficiency in glucocerebrosidase (GBA, a retaining β-glucosidase), and GBA constitutes the largest known genetic risk factor for Parkinson's disease. In past, animal models of have been generated treatment with mechanism-based inhibitors, conduritol B epoxide (CBE), cyclophellitol. Both compounds, however, also target other glycosidases, rendering generation interpretation such chemical knockout complicated. Here we demonstrate that cyclophellitol...
Abstract p27KIP1 (cyclin-dependent kinase inhibitor 1B, p27) is a member of the CIP/KIP family CDK (cyclin dependent kinase) regulators that inhibit cell cycle CDKs. p27 phosphorylation by CDK1/2, signals its recruitment to SCF SKP2 (S-phase associated protein 1 (SKP1)-cullin-SKP2) E3 ubiquitin ligase complex for proteasomal degradation. The nature binding and CKS1 was revealed SKP1-SKP2-CKS1-p27 phosphopeptide crystal structure. Subsequently, model hexameric CDK2-cyclin A-CKS1-p27-SKP1-SKP2...
Mutations in many members of the set human lysosomal glycoside hydrolases cause a wide range storage diseases. As result, much effort has been directed toward identifying pharmacological chaperones these enzymes. The majority candidate are active site-directed competitive iminosugar inhibitors but have met with limited success. first step an alternative class we explored potential small molecule mechanism-based reversible covalent to form transient enzyme-inhibitor adducts. By serial...
Parallel FluoPol-ABPP screenings on lysosomal β-glucosidase (GBA1) and α-glucosidase (GAA) revealed a N -9-phenanthrenyl-DNJ that inhibits GAA selectively is an interesting hit for the development of chaperones Pompe disease.
α-<sc>d</sc>-Gal-cyclophellitol cyclosulfamidate is a new class of neutral, conformationally-constrained competitive glycosidase inhibitor that stabilizes α-gal A and prevents its degradation both <italic>in vitro</italic> cellulo</italic> by mimicry the Michaelis complex conformation.
Gaucher disease (GD) is a lysosomal storage disorder caused by inherited deficiencies in β-glucocerebrosidase (GBA). Current treatments require rapid diagnosis and means of monitoring therapeutic efficacy, both which may be supported the use GBA-targeting activity-based probes (ABPs). Here, we report synthesis structural analysis range cyclophellitol epoxide aziridine inhibitors ABPs for GBA. We demonstrate their covalent mechanism-based mode action uncover binding new N-functionalised...
The lysosomal glycoside hydrolase β-glucocerebrosidase (GBA; sometimes called GBA1 or GC ase ) catalyses the hydrolysis of glycosphingolipids. Inherited deficiencies in GBA cause storage disorder Gaucher disease (GD). Consequently, is considerable medical interest, with continuous advances development inhibitors, chaperones and activity-based probes. new inhibitors requires a source active protein; however, majority structural mechanistic studies today rely on clinical enzyme-replacement...
The cell division cycle 25 phosphatases CDC25A, B and C regulate transitions by dephosphorylating residues in the conserved glycine-rich loop of CDKs to activate their activity. Here, we present cryo-EM structure CDK2-cyclin A complex with CDC25A at 2.7 Å resolution, providing a detailed structural analysis overall architecture key protein-protein interactions that underpin this 86 kDa complex. We further identify C-terminal helix is critical for formation. Sequence conservation suggests...
Abstract The cell division cycle 25 phosphatases CDC25A, B and C regulate transitions by dephosphorylating residues in the conserved glycine-rich motif of cyclin-dependent protein kinases (CDKs) to activate CDK activity. Here, we present cryogenic-electron microscopy (cryo-EM) structure CDK2-cyclin A complex with CDC25A at 2.91 Å resolution, providing a detailed structural analysis overall architecture key protein-protein interactions that underpin this 86 kDa complex. We further reveal an...