A5041531714- Nicotinic Acetylcholine Receptors Study
- Ion channel regulation and function
- Neuroscience and Neuropharmacology Research
- Insect and Pesticide Research
- Receptor Mechanisms and Signaling
- Antimicrobial Peptides and Activities
- Venomous Animal Envenomation and Studies
- Electrochemical Analysis and Applications
- Peroxisome Proliferator-Activated Receptors
- Cholinesterase and Neurodegenerative Diseases
- Photoreceptor and optogenetics research
- RNA Research and Splicing
- Bacteriophages and microbial interactions
- Biochemical and Structural Characterization
- Protein Degradation and Inhibitors
- Cellular transport and secretion
- Plant and animal studies
- Molecular Junctions and Nanostructures
- interferon and immune responses
- Lipid Membrane Structure and Behavior
- Insect and Arachnid Ecology and Behavior
- Silymarin and Mushroom Poisoning
- Adipose Tissue and Metabolism
- Oxidative Organic Chemistry Reactions
- Medicinal Plants and Neuroprotection
KU Leuven
2015-2024
HiQScreen (Switzerland)
2022
Laboratory of Molecular Genetics
2020
GABA(A) receptors are pentameric ligand-gated ion channels involved in fast inhibitory neurotransmission and allosterically modulated by the anxiolytic, anticonvulsant, sedative-hypnotic benzodiazepines. Here we show that prokaryotic homolog ELIC also is activated GABA benzodiazepines with effects comparable to those at receptors. Crystal structures reveal important features of recognition indicate benzodiazepines, depending on their concentration, occupy two possible sites ELIC. An...
Bites by elapid snakes (e.g. cobras) can result in life-threatening paralysis caused venom neurotoxins blocking neuromuscular nicotinic acetylcholine receptors. Here, we determine the cryo-EM structure of muscle-type Torpedo receptor complex with ScNtx, a recombinant short-chain α-neurotoxin. ScNtx is pinched between loop C on principal subunit and unique hairpin F complementary subunit, thereby access to neurotransmitter binding site. adopts mode that tilted toward forming wider network...
Cys-loop receptors (CLR) are pentameric ligand-gated ion channels that mediate fast excitatory or inhibitory transmission in the nervous system. Strychnine and d-tubocurarine (d-TC) neurotoxins have been highly instrumental decades of research on glycine (GlyR) nicotinic acetylcholine (nAChR), respectively. In this study we addressed question how molecular recognition strychnine d-TC occurs with high affinity yet low specificity towards diverse CLR family members. X-ray crystal structures...
Pentameric ligand-gated ion channels (pLGICs), such as nicotinic acetylcholine, glycine, γ-aminobutyric acid GABA(A/C) receptors, and the Gloeobacter violaceus channel (GLIC), are receptors that contain multiple allosteric binding sites for a variety of therapeutics, including general anesthetics. Here, we report x-ray crystal structure Erwinia chrysanthemi (ELIC) in complex with derivative chloroform, which reveals important features anesthetic recognition, involving at three different...
The 5‐HT 3 receptor is a pentameric serotonin‐gated ion channel, which mediates rapid excitatory neurotransmission and the target of therapeutically important class anti‐emetic drugs, such as granisetron. We report crystal structures binding protein engineered to recognize agonist serotonin antagonist granisetron with affinities comparable receptor. In serotonin‐bound structure, we observe hydrophilic interactions loop E‐binding site residues, might enable transitions channel opening....
Abstract Natural selection shapes protein solubility to physiological requirements and recombinant applications that require higher concentrations are often problematic. This raises the question whether of natural sequences can be improved. We here show an anti-correlation between number aggregation prone regions (APRs) in a sequence its solubility, suggesting mutational suppression APRs provides simple strategy increase solubility. mutations at specific positions within structure act as APR...
Partial agonists of the α4β2 nicotinic acetylcholine receptor (nAChR), such as varenicline, are therapeutically used in smoking cessation treatment. These drugs derive their therapeutic effect from fundamental molecular actions, which to desensitize nAChRs and induce channel opening with higher affinity, but lower efficacy than a full agonist at equal occupancy. Here, we report X-ray crystal structures unique binding protein (AChBP) annelid Capitella teleta , Ct-AChBP, complex varenicline or...
Significance We describe a previously unidentified family of prokaryote cyclic nucleotide-modulated ion channels. In eukaryotes, CNG channels play important roles in signal transduction as they mediate the passage ions across cell membrane response to cAMP or cGMP. this study, we demonstrate that two homologs, AmaK and SthK, can be expressed purified from Escherichia coli membranes. reveal SthK has functional properties closely resemble eukaryote HCN is gated by AMP, but not GMP, selects K +...
Cyclic nucleotide-sensitive ion channels are molecular pores that open in response to cAMP or cGMP, which universal second messengers. Binding of a cyclic nucleotide the carboxyterminal binding domain (CNBD) these is thought cause conformational change promotes channel opening. The C-linker domain, connects pore this CNBD, plays an important role coupling ligand Current structural insight into mechanism mainly derives from X-ray crystal structures C-linker/CNBD hyperpolarization-activated...
Nicotinic acetylcholine receptors (nAChRs) belong to the family of pentameric ligand-gated ion channels and mediate fast excitatory transmission in central peripheral nervous systems. Among different existing receptor subtypes, homomeric α7 nAChR has attracted considerable attention because its possible implication several neurological psychiatric disorders, including cognitive decline associated with Alzheimer's disease or schizophrenia. Allosteric modulators are particular interest as...
Significance Cys-loop receptors belong to a family of ion channels that are involved in fast synaptic transmission. Allosteric modulators hold therapeutic potential as they tweak receptor function while preserving the normal fluctuations neurotransmitter signaling at synapse. Here, we take advantage model receptor, Erwinia ligand-gated channel (ELIC). We determined cocrystal structures ELIC complex with chlorpromazine (IC 50 , ∼160 μM) and its brominated derivative bromopromazine, which...
Pentameric ligand-gated ion channels (pLGICs) are crucial mediators of electrochemical signal transduction in various organisms from bacteria to humans. Lipids play an important role regulating pLGIC function, yet the structural bases for specific pLGIC-lipid interactions remain poorly understood. The bacterial channel ELIC recapitulates several properties eukaryotic pLGICs, including activation by neurotransmitter GABA and binding modulation lipids, offering a simplified model system...
Pentameric ligand-gated ion channels (pLGICs) or Cys-loop receptors are involved in fast synaptic signaling the nervous system. Allosteric modulators bind to sites that remote from neurotransmitter binding site, but modify coupling of ligand channel opening. In this study, we developed nanobodies (single domain antibodies), which functionally active as allosteric modulators, and solved co-crystal structures prokaryote (Erwinia) ELIC bound either a positive negative modulator. The nanobody...
<h3>Background:</h3> Peroxisome biogenesis disorders are a clinically and genetically heterogeneous group of very severe autosomal recessive caused by impaired peroxisome biogenesis. The prototype this is the cerebro-hepato-renal syndrome Zellweger. <h3>Methods results:</h3> Here we report patient with Zellweger syndrome, who presented at age 3 months icterus, dystrophy, axial hypotonia, facial dysmorphy, posterior embryotoxon, hepatomegaly. Abnormal findings metabolic screening tests...
TRPV3 is a thermosensitive ion channel primarily expressed in epithelial tissues of the skin, nose, and tongue. The has been implicated environmental thermosensation, hyperalgesia inflamed tissues, skin sensitization, hair growth. Although transient receptor potential (TRP) research vastly increased our understanding physiological mechanisms nociception molecular mechanics these channels are still largely elusive. In order to better comprehend functional properties mechanism action TRP...
Cys-loop receptors are membrane spanning ligand-gated ion channels involved in fast excitatory and inhibitory neurotransmission. Three-dimensional structures of these channels, determined by X-ray crystallography or electron microscopy, have revealed valuable information regarding the molecular mechanisms underlying ligand recognition, channel gating conductance. To extend validate current insights, we here present promising candidates for further structural studies. We report biochemical...
Here we report a patient with Zellweger syndrome, who presented at the age of 3 months icterus, dystrophy, axial hypotonia, and hepatomegaly. Abnormal findings metabolic screening tests included hyperbilirubinaemia, hypoketotic dicarboxylic aciduria, increased C(26:0) decreased C(22:0) plasma levels, strongly reduced plasmalogen concentrations. In fibroblasts, both peroxisomal α- β-oxidation were impaired. Liver histology revealed bile duct paucity, cholestasis, arterial hyperplasia, very...
Neonicotinoids, sometimes called ‘neonics’, are a class of insecticides targeting neuronal nicotinic acetylcholine receptors, which belong to the family pentameric ligand-gated ion channels (pLGICs) or Cys-loop receptors. The widespread application these neurotoxic in agriculture is tied worldwide decline bee populations, due their sublethal effects on memory, behavior and reproduction. In 2018, member states European Union, agreed ban most neonicotinoids, with exemption for greenhouses....
Abstract Pentameric ligand-gated ion channels (pLGICs) are crucial mediators of electrochemical signal transduction from bacteria to humans. Lipids play an important role in regulating pLGIC function, yet the structural basis for specific pLGIC-lipid interactions remains poorly understood. The bacterial channel ELIC recapitulates several properties eukaryotic pLGICs, including activation by neurotransmitter GABA and sensitivity lipids, offering a simplified model system structure-function...