A5030445850- Trace Elements in Health
- Drug Transport and Resistance Mechanisms
- Metal complexes synthesis and properties
- Advanced Electron Microscopy Techniques and Applications
- Insect and Pesticide Research
- Toxin Mechanisms and Immunotoxins
- Bacillus and Francisella bacterial research
- Bacteriophages and microbial interactions
- Ion Transport and Channel Regulation
- ATP Synthase and ATPases Research
- Ion Channels and Receptors
- Electron and X-Ray Spectroscopy Techniques
- Entomopathogenic Microorganisms in Pest Control
- Antibiotic Resistance in Bacteria
- Force Microscopy Techniques and Applications
- Advanced Fluorescence Microscopy Techniques
- Yersinia bacterium, plague, ectoparasites research
- Vector-borne infectious diseases
- Ion channel regulation and function
- Plant Micronutrient Interactions and Effects
- Boron and Carbon Nanomaterials Research
- Radiopharmaceutical Chemistry and Applications
- Metabolism and Genetic Disorders
- Insect Resistance and Genetics
- Plant Stress Responses and Tolerance
Max Planck Institute of Molecular Physiology
2018-2025
Aarhus University
2012-2024
University of Oxford
2016-2023
Danish National Research Foundation
2012-2015
National Research Foundation
2013-2014
Abstract Selecting particles from digital micrographs is an essential step in single-particle electron cryomicroscopy (cryo-EM). As manual selection of complete datasets—typically comprising thousands particles—is a tedious and time-consuming process, numerous automatic particle pickers have been developed. However, non-ideal datasets pose challenge to picking. Here we present the picking software crYOLO which based on deep-learning object detection system You Only Look Once (YOLO). After...
Cryogenic-electron tomography enables the visualization of cellular environments in extreme detail, however, tools to analyze full amount information contained within these densely packed volumes are still needed. Detailed analysis macromolecules through subtomogram averaging requires particles first be localized tomogram volume, a task complicated by several factors including low signal noise ratio and crowding space. Available methods for this suffer either from being error prone or...
Proteins that contain metal cofactors are expected to be highly radiation sensitive since the degree of X-ray absorption correlates with presence high-atomic-number elements and energy. To explore effects local damage in serial femtosecond crystallography (SFX), Clostridium ferredoxin was used as a model system. The protein contains two [4Fe-4S] clusters serve probes for radiation-induced electronic structural changes. High-dose room-temperature SFX datasets were collected at Linac Coherent...
Abstract In mammals, the kidney plays an essential role in maintaining blood homeostasis through selective uptake, retention or elimination of toxins, drugs and metabolites. Organic anion transporters (OATs) are responsible for recognition metabolites toxins nephron their eventual urinary excretion. Inhibition OATs is used therapeutically to improve drug efficacy reduce nephrotoxicity. The founding member renal organic transporter family, OAT1 (also known as SLC22A6), uses export...
Lifeact is a short actin-binding peptide that used to visualize filamentous actin (F-actin) structures in live eukaryotic cells using fluorescence microscopy. However, this popular probe has been shown alter cellular morphology by affecting the structure of cytoskeleton. The molecular basis for such artefacts poorly understood. Here, we determined high-resolution Lifeact–F-actin complex electron cryo-microscopy (cryo-EM). reveals interacts with hydrophobic binding pocket on F-actin and...
Canonical transient receptor potential channels (TRPC) are involved in receptor-operated and/or store-operated Ca2+ signaling. Inhibition of TRPCs by small molecules was shown to be promising treating renal diseases. In cells, the regulated calmodulin (CaM). Molecular details both CaM and drug binding have remained elusive so far. Here, we report structures TRPC4 complex with three pyridazinone-based inhibitors CaM. The reveal that all bind same cavity voltage-sensing-like domain allow us...
The human copper exporters ATP7A and ATP7B contain domains common to all P-type ATPases as well class-specific features such six sequential heavy-metal binding (HMBD1-HMBD6) a type-specific constellation of transmembrane helices. Despite the medical significance related Menkes Wilson diseases, respectively, structural information has only been available for isolated, soluble domains. Here we present homology models based on existing structures recently determined structure homologous LpCopA...
Abstract Toxin complex (Tc) toxins are virulence factors of pathogenic bacteria. Tcs composed three subunits: TcA, TcB and TcC. TcA facilitates receptor–toxin interaction membrane permeation, TcC form a toxin-encapsulating cocoon. While the mechanisms holotoxin assembly pore formation have been described, little is known about receptor binding TcAs. Here, we identify heparins/heparan sulfates Lewis antigens as receptors for different TcAs from insect human pathogens. Glycan array screening...
Tc toxins are pore-forming virulence factors of many pathogenic bacteria. Following pH-induced conformational changes, they perforate the target membrane like a syringe to translocate toxic enzymes into cell. Although this complex transformation has been structurally well studied, reaction pathway and resulting temporal evolution have remained elusive. We used an integrated biophysical approach monitor prepore-to-pore transition found time ~30 hours for complete transition. show two...
Abstract Tc toxins are bacterial protein complexes that inject cytotoxic enzymes into target cells using a syringe-like mechanism. composed of membrane translocator and cocoon encapsulates toxic enzyme. The enzyme varies between from different species is not conserved. Here, we investigate whether the can be replaced by other small proteins origin properties, namely Cdc42, herpes simplex virus ICP47, Arabidopsis thaliana iLOV, Escherichia coli DHFR, Ras-binding domain CRAF kinase, TEV...
Abstract Disease-causing bacteria secrete numerous toxins to invade and subjugate their hosts. Unlike many smaller toxins, the secretion machinery of most large remains enigmatic. By combining genomic editing, proteomic profiling cryo-electron tomography insect pathogen Yersinia entomophaga , we demonstrate that a specialized subset these cells produces complex toxin cocktail, including nearly ribosome-sized Tc YenTc, which is subsequently exported by controlled cell lysis using...
Membrane proteins are key players in biological systems, mediating signalling events and the specific transport of e.g. ions metabolites. Consequently, membrane targeted by a large number currently approved drugs. Understanding their functions molecular mechanisms is greatly dependent on structural information, not least complexes with functionally or medically important ligands. Structure determination, however, hampered difficulty obtaining well diffracting, macroscopic crystals. Here,...
Abstract Selecting particles from digital micrographs is an essential step in single particle electron cryomicroscopy (cryo-EM). Since manual selection of complete datasets typically comprising many thousands a tedious and time-consuming process, automatic pickers have been developed the past few decades. However, non-ideal pose challenge to picking. Here, we present novel automated picking software called crYOLO, which based on deep learning object detection system “You Only Look Once”...
Abstract Tc toxins are virulence factors of many insects and human pathogenic bacteria. They attach as soluble prepores to receptors on host cells following acidification in the late endosome, perforate cell membrane like a syringe translocate toxic enzymes into through their pore-forming channel. Although this complex transformation has been structurally well studied, functional aspects large-scale rearrangement, such reaction pathway with possible intermediate states resulting temporal...
Abstract Lifeact is a short actin-binding peptide that used to visualize filamentous actin (F-actin) structures in live eukaryotic cells using fluorescence microscopy. However, this popular probe has been shown alter cellular morphology by affecting the structure of cytoskeleton. The molecular basis for such artefacts poorly understood. Here, we determined high-resolution Lifeact–F-actin complex electron cryo-microscopy. reveals interacts with hydrophobic binding pocket on F-actin and...