A5054630928- Microtubule and mitosis dynamics
- Cardiac electrophysiology and arrhythmias
- Photosynthetic Processes and Mechanisms
- Genomics and Phylogenetic Studies
- Ion channel regulation and function
- DNA Repair Mechanisms
- Genomics and Chromatin Dynamics
- Microbial Metabolism and Applications
- Advanced Electron Microscopy Techniques and Applications
- Bacteriophages and microbial interactions
- Enzyme Structure and Function
- Bacterial Genetics and Biotechnology
- Protist diversity and phylogeny
- Fungal and yeast genetics research
- Peptidase Inhibition and Analysis
- Advanced NMR Techniques and Applications
- 14-3-3 protein interactions
- Epigenetics and DNA Methylation
- Nicotinic Acetylcholine Receptors Study
- Nuclear Structure and Function
- Probiotics and Fermented Foods
- Chemical Synthesis and Analysis
- Natural product bioactivities and synthesis
- Ubiquitin and proteasome pathways
- Biochemical and Structural Characterization
Heidelberg University
2021-2025
DKFZ-ZMBH Alliance
2022-2024
Utrecht University
2019-2023
Abstract Antibiotics that use novel mechanisms are needed to combat antimicrobial resistance 1–3 . Teixobactin 4 represents a new class of antibiotics with unique chemical scaffold and lack detectable resistance. targets lipid II, precursor peptidoglycan 5 Here we unravel the mechanism teixobactin at atomic level using combination solid-state NMR, microscopy, in vivo assays molecular dynamics simulations. The enduracididine C-terminal headgroup specifically binds pyrophosphate-sugar moiety...
Antimicrobial resistance is a leading mortality factor worldwide. Here, we report the discovery of clovibactin, an antibiotic isolated from uncultured soil bacteria. Clovibactin efficiently kills drug-resistant Gram-positive bacterial pathogens without detectable resistance. Using biochemical assays, solid-state nuclear magnetic resonance, and atomic force microscopy, dissect its mode action. blocks cell wall synthesis by targeting pyrophosphate multiple essential peptidoglycan precursors...
Abstract The natural antibiotic teixobactin kills pathogenic bacteria without detectable resistance. difficult synthesis and unfavourable solubility of require modifications, yet insufficient knowledge on its binding mode impedes the hunt for superior analogues. Thus far, teixobactins are assumed to kill by cognate cell wall precursors (Lipid II III). Here we present in cellular membranes using solid-state NMR, microscopy, affinity assays. We solve structure complex formed an improved...
Abstract The gamma-tubulin ring complex (γ-TuRC) is the principal microtubule nucleation template in vertebrates. Recent cryo-EM reconstructions visualized intricate quaternary structure of γ-TuRC, containing more than thirty subunits, raising fundamental questions about γ-TuRC assembly and role actin as an integral part complex. Here, we reveal structural mechanism underlying modular identify a functional nucleation. During assembly, GCP6-stabilized core comprising GCP2-3-4-5-4-6 expanded...
The γ-tubulin ring complex (γ-TuRC) is a structural template for de novo microtubule assembly from α/β-tubulin units. isolated vertebrate γ-TuRC assumes an asymmetric, open structure deviating geometry, suggesting that closure may underlie regulation of nucleation. Here, we isolate native γ-TuRC-capped microtubules Xenopus laevis egg extract nucleated through the RanGTP-induced pathway spindle and determine their cryo-EM structure. Intriguingly, minus end-bound only partially closed...
Abstract The γ-tubulin ring complex (γ-TuRC) is a structural template for controlled nucleation of microtubules from α/β-tubulin heterodimers. At the cytoplasmic side yeast spindle pole body, CM1-containing receptor protein Spc72 promotes γ-TuRC assembly seven small complexes (γ-TuSCs) and recruits microtubule polymerase Stu2, yet their molecular interplay remains unclear. Here, we determine cryo-EM structure Candida albicans unit at 3.6 Å resolution, revealing how assembled conformationally...
Abstract The γ-tubulin ring complex (γ-TuRC) acts as a structural template for microtubule formation at centrosomes, associating with two main compartments: the pericentriolar material and centriole lumen. In material, γ-TuRC is involved in organization, while function of lumenal pool remains unclear. conformational landscape γ-TuRC, which crucial its activity, centrosomal anchoring mechanisms, determine activity turnover, are not understood. Using cryo-electron tomography, we analyze...
Abstract C-type inactivation is of great physiological importance in voltage-activated K + channels (Kv), but its structural basis remains unresolved. Knowledge about has been largely deduced from the bacterial channel KcsA, whose selectivity filter constricts under inactivating conditions. However, highly sensitive to molecular environment, which different Kv than KcsA. In particular, a glutamic acid residue at position 71 along pore helix KcsA substituted by valine conserved most channels,...
Abstract In mitosis, the augmin complex binds to spindle microtubules recruit γ-tubulin ring (γ-TuRC), principal microtubule nucleator, for formation of branched microtubules. Our understanding augmin-mediated branching is hampered by lack structural information on complex. Here, we elucidate molecular architecture and conformational plasticity using an integrative biology approach. The elongated structure characterised extensive coiled-coil segments comprises two elements with distinct but...
De novo macrocyclic peptides, derived using selection technologies such as phage and mRNA display, present unique unexpected solutions to challenging biological problems. This is due in part their unusual folds, which are able side chains ways not available canonical structures α-helices β-sheets. Despite much recent interest these molecules, folding binding behavior remains poorly characterized. In this work, we cocrystallization, docking, solution NMR of three de peptides that all bind...
Cryo-electron microscopy recently resolved the structure of vertebrate γ-tubulin ring complex (γ-TuRC) purified from Xenopus laevis egg extract and human cells to near-atomic resolution. These studies clarified arrangement stoichiometry γ-TuRC components revealed that one molecule actin small protein MZT1 are embedded into complex. Based on this structural census core components, we developed a recombinant expression system for reconstitution purification insect cells. The recapitulates...
Abstract Microtubules are protein cylinders with functions in cell motility, signal sensing, organization, intracellular transport, and chromosome segregation. One of the key properties microtubules is their dynamic architecture, allowing them to grow shrink length by adding or removing copies basic subunit, heterodimer αβ‐tubulin. In higher eukaryotes, de novo assembly from αβ‐tubulin initiated a 2 MDa multi‐subunit complex, gamma‐tubulin ring complex (γ‐TuRC). For many years, structure...
Antimicrobial resistance is a leading mortality factor worldwide. Here we report the discovery of clovibactin, new antibiotic, isolated from uncultured soil bacteria. Clovibactin efficiently kills drug-resistant bacterial pathogens without detectable resistance. Using biochemical assays, solid-state NMR, and atomic force microscopy, dissect its mode action. blocks cell wall synthesis by targeting pyrophosphate multiple essential peptidoglycan precursors (C 55 PP, Lipid II, WTA ). uses an...
Abstract Microtubules, essential components of the cytoskeleton, are assembled from α/β-tubulin subunits by γ-tubulin ring complex (γ-TuRC). Over last five years, cryo-electron microscopy studies have advanced our structural and mechanistic understanding this process elucidating structures γ-TuRC different organisms and, very recently, after microtubule nucleation under varying conditions.
ABSTRACT A large class of K + channels display a time-dependent phenomenon called C-type inactivation whereby prolonged activation by an external stimulus leads to non-conductive conformation the selectivity filter. is great physiological importance particularly in voltage-activated (Kv), affecting firing patterns neurons and shaping cardiac action potentials. While understanding molecular basis has direct impact on human health, its structural remains unresolved. Knowledge about been...