A5027656570- Protein Structure and Dynamics
- Enzyme Structure and Function
- RNA and protein synthesis mechanisms
- Heat shock proteins research
- Chemical Synthesis and Analysis
- Ubiquitin and proteasome pathways
- Bacterial Genetics and Biotechnology
- Toxin Mechanisms and Immunotoxins
- Bacteriophages and microbial interactions
- Microtubule and mitosis dynamics
- Lipid Membrane Structure and Behavior
- Monoclonal and Polyclonal Antibodies Research
- Advanced Breast Cancer Therapies
- Biochemical and Structural Characterization
- Receptor Mechanisms and Signaling
- Cancer-related Molecular Pathways
- Synthesis and Characterization of Heterocyclic Compounds
- Antibiotic Resistance in Bacteria
- thermodynamics and calorimetric analyses
- Mass Spectrometry Techniques and Applications
- DNA Repair Mechanisms
- Click Chemistry and Applications
- Field-Flow Fractionation Techniques
- Glycosylation and Glycoproteins Research
- PARP inhibition in cancer therapy
University of Basel
2015-2025
University of Cambridge
2005-2021
University of Oxford
2010-2018
Genomics (United Kingdom)
2010-2018
Applied BioPhysics (United States)
2016
Medical Research Council
2003-2007
Hutchison/MRC Research Centre
2004-2005
University of Wisconsin–Madison
1983-1986
Human CA150, a transcriptional activator, binds to and is co-deposited with huntingtin during Huntington's disease. The second WW domain of CA150 three-stranded beta-sheet that folds in vitro microseconds forms amyloid fibers under physiological conditions. We found from exhaustive alanine scanning studies fibrillation this begins its denatured conformations, we identified subset residues critical for fibril formation. used high-resolution magic-angle-spinning NMR on site-specific...
Here we show a seven-step chemical synthesis of DNA-encoded macrocycle library (DEML) on DNA. Inspired by polyketide and mixed peptide-polyketide natural products, the was designed to incorporate rich backbone diversity. Achieving this diversity, however, comes at cost custom bifunctional building block libraries. This study outlines importance careful retrosynthetic design in libraries, while revealing areas where new DNA synthetic methods are needed.
Urinary tract infections (UTIs), predominantly caused by uropathogenic Escherichia coli (UPEC), belong to the most prevalent infectious diseases worldwide. The attachment of UPEC host cells is mediated FimH, a mannose-binding adhesin at tip bacterial type 1 pili. To date, UTIs are mainly treated with antibiotics, leading ubiquitous problem increasing resistance against currently available antimicrobials. Therefore, new treatment strategies urgently needed. Here, we describe development an...
Conformation and dynamics of a chaperone-client interaction at the atomic level show basic underlying mechanism.
Various kinases, including a cyclin-dependent kinase (CDK) family member, regulate the growth and functions of primary cilia, which perform essential roles in signaling development. Neurological disorders linked to CDK-Like (CDKL) proteins suggest that these underexplored kinases may have similar functions. Here, we present crystal structures human CDKL1, CDKL2, CDKL3, CDKL5, revealing their evolutionary divergence from CDK mitogen-activated protein (MAPKs), an unusual ?J helix important for...
The universal second messenger cyclic di-GMP (cdG) is involved in the regulation of a diverse range cellular processes bacteria. intracellular concentration dinucleotide determined by opposing actions diguanylate cyclases and cdG-specific phosphodiesterases (PDEs). Whereas most PDEs have accessory domains that are their activity, regulatory mechanism this class enzymes has remained unclear. Here, we use biophysical functional analyses to show isolated EAL domain PDE from Escherichia coli...
Synthetic lethality between the clinically approved noncancer drugs metformin and syrosingopine specifically kills cancer cells.
The chaperone Trigger Factor (TF) from Escherichia coli forms a dimer at cellular concentrations. While the monomer structure of TF is well known, spatial arrangement this dimeric storage form has remained unclear. Here, we determine its by combination high-resolution NMR spectroscopy and biophysical methods. symmetric head-to-tail dimer, where ribosome binding domain in contact with substrate domain, while peptidyl-prolyl isomerase contributes only slightly to affinity. highly dynamic, two...
BRCA2 controls RAD51 recombinase during homologous DNA recombination (HDR) through eight evolutionarily conserved BRC repeats, which individually engage via the motif Phe-x-x-Ala. Using structure-guided molecular design, templated on a monomeric thermostable chimera between human and archaeal RadA, we identify CAM833, 529 Da orthosteric inhibitor of RAD51:BRC with Kd 366 nM. The quinoline CAM833 occupies hotspot, Phe-binding pocket methyl substituted α-methylbenzyl group Ala-binding pocket....
Conventional cooperative protein folding invokes discrete ensembles of native and denatured state structures in separate free-energy wells. Unimodal noncooperative ("downhill") folding, however, proposes an ensemble states occupying a single well for proteins at >/=4 x 10(4) s(-1) 298 K. It is difficult to falsify unimodal mechanisms such fast by standard equilibrium experiments because both can present the same time-averaged structural, spectroscopic, thermodynamic properties when time...
Abstract Signal transmission and regulation of G-protein-coupled receptors (GPCRs) by extra- intracellular ligands occurs via modulation complex conformational equilibria, but their exact kinetic details underlying atomic mechanisms are unknown. Here we quantified these dynamic equilibria in the β 1 -adrenergic receptor its apo form seven ligand complexes using H/ 15 N NMR spectroscopy. We observe three major exchanging conformations: an inactive conformation ( C i ), a preactive p ) active...
Summary Fluorescent proteins and peptide tags are essential tools in cellular biology, but can alter the biochemical properties of target proteins. Biomolecular condensates, which have emerged as key principles organization, suggested to provide robustness cells, yet they also respond sensitively small changes environmental conditions—or tagging their components, our findings suggest. Here, we investigated effects sixteen widely used on condensate formation various model organisms, vitro ,...
The WW domains are small proteins that contain a three-stranded, antiparallel β-sheet. 40-residue murine FBP28 domain rapidly formed twirling ribbon-like fibrils at physiological temperature and pH, with morphology typical of amyloid fibrils. These ribbons were unusually wide well ordered, making them highly suitable for structural studies. Their x-ray electron-diffraction patterns displayed the characteristic fiber 0.47-nm reflection cross-β diffraction signature. Both conventional electron...
The mammalian SPRY domain- and SOCS box-containing proteins, SPSB1 to SPSB4, belong the box family of E3 ubiquitin ligases. Substrate recognition sites for domain are identified only human Par-4 (ELNNNL) Drosophila orthologue GUSTAVUS binding DEAD-box RNA helicase VASA (DINNNN). To further investigate this consensus motif, we determined crystal structures SPSB1, SPSB2, as well their modes affinities both VASA. Mutation each three Asn residues in abrogated all SPSB while changing EL DI...
CDK16 (also known as PCTAIRE1 or PCTK1) is an atypical member of the cyclin-dependent kinase (CDK) family that has emerged a key regulator neurite outgrowth, vesicle trafficking and cancer cell proliferation. activated through binding to cyclin Y via phosphorylation-dependent 14-3-3 interaction unique consensus substrate phosphorylation motif compared with conventional CDKs. To elucidate structure inhibitor-binding properties this CDK, we screened domain against different inhibitor libraries...
Trimeric chaperone Skp activates by an unprecedented mechanism, with folding from a disordered state coupled to trimerization.
The TCR-mediated activation of T cells expressing the TCR Vγ9Vδ2 relies on an innate-like mechanism involving butyrophilin 3A1, 3A2 and 2A1 molecules phospho-antigens, without participation classical antigen-presenting molecules. Whether also recognize complexes composed antigens in adaptive-like manner is unknown. Here, we identify MR1-autoreactive Vγ9Vδ2. This MR1-restricted response antigen- CDR3δ-dependent butyrophilin-independent. gene transfer reconstitutes MR1-antigen recognition,...
Significance FIC-domain enzymes are found in all kingdoms of life and catalyze posttranslational modifications various target proteins to modulate their function. Because the vast majority Fic expressed an inhibited form, physiological importance has escaped attention for a long time. This article reveals autonomous mechanism inhibition relief class III proteins, which hinges on autoadenylylation inhibitory helix. process occurs cis , enzyme constitutes molecular timer that operates...