A5021142555- Enzyme Structure and Function
- Protein Structure and Dynamics
- Molecular spectroscopy and chirality
- RNA and protein synthesis mechanisms
- RNA Research and Splicing
- Biochemical and Molecular Research
- RNA modifications and cancer
- Click Chemistry and Applications
- Monoclonal and Polyclonal Antibodies Research
- Inflammasome and immune disorders
- Microtubule and mitosis dynamics
- Neuroscience and Neuropharmacology Research
- Radiopharmaceutical Chemistry and Applications
- Chemical Synthesis and Analysis
- Streptococcal Infections and Treatments
- Erythrocyte Function and Pathophysiology
- Computational Drug Discovery Methods
- Ferrocene Chemistry and Applications
- Toxin Mechanisms and Immunotoxins
- Synthesis of heterocyclic compounds
- Cancer therapeutics and mechanisms
- Plant biochemistry and biosynthesis
- GABA and Rice Research
- Advanced biosensing and bioanalysis techniques
- Biochemical and Structural Characterization
University of Oxford
2015-2023
MRC Laboratory of Molecular Biology
2017-2023
Freie Universität Berlin
2013-2022
Genomics England
2015-2018
Genomics (United Kingdom)
2018
Centre for Human Genetics
2017
Nuffield Health
2016
Cyclin G associated kinase (GAK) emerged as a promising drug target for the treatment of viral infections. However, no potent and selective GAK inhibitors have been reported in literature to date. This paper describes discovery isothiazolo[5,4-b]pyridines inhibitors, with most congeners displaying low nanomolar binding affinity GAK. Cocrystallization experiments revealed that these compounds behaved classic type I ATP-competitive inhibitors. In addition, we demonstrated exhibit activity...
Prolonged drug residence times may result in longer-lasting efficacy, improved pharmacodynamic properties, and "kinetic selectivity" over off-targets with high dissociation rates. However, few strategies have been elaborated to rationally modulate time thereby integrate this key property into the development process. Herein, we show that interaction between a halogen moiety on an inhibitor aromatic residue target protein can significantly increase time. By using of serine/threonine kinase...
Abstract NLRP3 induces caspase-1-dependent pyroptotic cell death to drive inflammation. Aberrant activity of occurs in many human diseases. activation ASC polymerization into a single, micron-scale perinuclear punctum. Higher resolution imaging this signaling platform is needed understand how it pyroptosis. Here, we apply correlative cryo-light microscopy and cryo-electron tomography visualize ASC/caspase-1 NLRP3-activated cells. The puncta are composed branched filaments, with tubular core...
Fast synaptic neurotransmission in the vertebrate central nervous system relies primarily on ionotropic glutamate receptors (iGluRs), which drive neuronal excitation, and type A γ-aminobutyric acid (GABA Rs), are responsible for inhibition. However, GluD1 receptor, an iGluR family member, is present at both excitatory inhibitory synapses. Whether how activation may affect unknown. In this work, by using a combination of biochemical, structural, functional analyses, we demonstrate that binds...
Yeast U5 small nuclear ribonucleoprotein particle (snRNP) is assembled via a cytoplasmic precursor that contains the U5-specific Prp8 protein but lacks Brr2 helicase. Instead, pre-U5 snRNP includes Aar2 not found in mature or spliceosomes. Aar2p and Brr2p bind competitively to C-terminal region of Prp8p comprises consecutive RNase H-like Jab1/MPN-like domains. To elucidate molecular basis for this competition, we determined crystal structure complex with H Jab1/MPN binds on one side domain...
Abstract Elaborate regulatory networks of the Bone Morphogenetic Protein (BMP) pathways ensure precise signalling outcome during cell differentiation and tissue homeostasis. Here, we identified IRS4 as a novel regulator BMP signal transduction provide molecular insights how it integrates into pathway. We found that interacts with receptor BMPRII specifically targets Smad1 for proteasomal degradation consequently leading to repressed BMP/Smad in C2C12 myoblasts while concomitantly activating...
The ability to incorporate a desired functionality into proteins of interest in site-specific manner can provide powerful tools for investigating biological systems and creating therapeutic conjugates. However, there are not any universal methods that be applied all proteins, it is thus important explore the chemical strategy protein modification. In this paper, we developed new reactive peptide tag/probe pair system covalent labeling. This method relies on recognition-driven reaction tag...
In eukaryotes, the removal of nuclear noncoding sequences (pre-mRNA splicing) is catalyzed by spliceosome, which consists five ribonucleoprotein particles (U1, U2, U4, U5 and U6 snRNPs, each with a respective snRNA) plethora protein factors that aid spliceosomal maturation, assembly, activation disassembly. Recently, snRNP maturation factor Aar2p from baker's yeast has been characterized structurally biochemically. binds to RNaseH (RH) Jab1/MPN domains highly conserved U5-specific Prp8p,...
Small nuclear ribonucleoprotein complexes (snRNPs) represent the main subunits of spliceosome. While assembly snRNP core particles has been well characterized, comparably little is known incorporation snRNP-specific proteins and mechanisms recycling. U5 in yeast requires binding Aar2 protein to Prp8p as a placeholder preclude premature SNRNP200 helicase, but role human AAR2 homolog not yet investigated detail. Here, crystal structure complex with RNase H-like domain U5-specific PRPF8 (PRP8F...
Abstract Längere Verweilzeiten vom Wirkstoff am Zielmolekül (Target) können zu länger anhaltender Arzneimittelwirksamkeit, verbesserten pharmakodynamischen Eigenschaften und kinetischer Selektivität gegenüber Antitargets mit schnellen Dissoziationsraten führen. Bisher wurden nur wenige Strategien gefunden, um die Verweilzeit des Wirkstoffs rational modulieren dadurch diese Schlüsseleigenschaft in den Medikamentenentwicklungsprozess integrieren. Die Wechselwirkung zwischen einem Halogenrest...
ABSTRACT Prolonged drug residence times may result in longer lasting efficacy, improved pharmacodynamic properties and “kinetic selectivity” over off-targets with fast dissociation rates. However, few strategies have been elaborated to rationally modulate time thereby integrate this key property into the development process. Here, we show that interaction between a halogen moiety on an inhibitor aromatic residue target protein can significantly increase time. By using of serine/threonine...