A5071980350- Cholinesterase and Neurodegenerative Diseases
- Computational Drug Discovery Methods
- Enzyme-mediated dye degradation
- melanin and skin pigmentation
- RNA and protein synthesis mechanisms
- Cellular transport and secretion
- Enzyme Structure and Function
- Pesticide Exposure and Toxicity
- Lipid Membrane Structure and Behavior
- Photosynthetic Processes and Mechanisms
- Advanced Fluorescence Microscopy Techniques
- Advanced Electron Microscopy Techniques and Applications
- Dye analysis and toxicity
- Identification and Quantification in Food
- Semiconductor materials and devices
- Microbial Metabolism and Applications
- Photoreceptor and optogenetics research
- Metal-Catalyzed Oxygenation Mechanisms
- Light effects on plants
- Metalloenzymes and iron-sulfur proteins
- X-ray Spectroscopy and Fluorescence Analysis
- Lysosomal Storage Disorders Research
- Enzyme function and inhibition
- Luminescence Properties of Advanced Materials
- Chemical synthesis and alkaloids
Institut de Biologie Structurale
2015-2025
CEA Grenoble
2016-2025
Commissariat à l'Énergie Atomique et aux Énergies Alternatives
2016-2025
Centre National de la Recherche Scientifique
2016-2025
Université Grenoble Alpes
2016-2025
Inserm
2024
Sorbonne Paris Cité
2024
Université Paris Cité
2024
Université Paris Sciences et Lettres
2019-2021
Institut Curie
2019-2021
Structure-based virtual screening of two libraries containing 567 981 molecules was used to discover novel, selective BuChE inhibitors, which are potentially superior symptomatic treatments in late-stage Alzheimer's disease. Compound 16 identified as a highly submicromolar inhibitor (huBuChE IC50 = 0.443 μM) with high permeability the PAMPA-BBB model. The X-ray crystal structure huBuChE complex revealed atomic-level interactions and offers opportunities for further development series.
Abstract Phytochromes are photoreceptor proteins that transmit a light signal from photosensory region to an output domain. Photoconversion involves protein conformational changes whose nature is not fully understood. Here, we use time-resolved X-ray scattering and optical spectroscopy study the kinetics of structural in full-length cyanobacterial phytochrome truncated form with no spectroscopic signals on µs/ms timescale largely independent presence On longer time-scales, large differences...
Radiation damage limits the accuracy of macromolecular structures in X-ray crystallography. Cryogenic (cryo-) cooling reduces global radiation rate and, therefore, became method choice over past decades. The recent advent serial crystallography, which spreads absorbed energy many crystals, thereby reducing damage, has rendered room temperature (RT) data collection more practical and also extendable to microcrystals, both enabling requiring study specific at RT. Here, we performed sequential...
Abstract Endosomal sorting complexes for transport-III (ESCRT-III) assemble in vivo onto membranes with negative Gaussian curvature. How membrane shape influences ESCRT-III polymerization and how shapes is yet unclear. Human core proteins, CHMP4B, CHMP2A, CHMP2B CHMP3 are used to address this issue vitro by combining nanotube pulling experiments, cryo-electron tomography AFM. We show that CHMP4B filaments preferentially bind flat or tubes positive mean Both CHMP2A/CHMP3 on positively curved...
Abstract Reversibly switchable fluorescent proteins (RSFPs) serve as markers in advanced fluorescence imaging. Photoswitching from a non-fluorescent off - state to on involves trans -to- cis chromophore isomerization and proton transfer. Whereas excited-state events the ps timescale have been structurally characterized, conformational changes slower timescales remain elusive. Here we describe off-to-on photoswitching mechanism RSFP rsEGFP2 by using combination of time-resolved serial...
Darobactin A is a ribosomally synthesized, post-translationally modified peptide (RiPP) with potent and broad-spectrum anti-Gram-negative antibiotic activity. The structure of darobactin characterized by an ether C–C crosslinking. However, the specific mechanism crosslink formation, especially crosslink, remains elusive. Here, using in vitro enzyme assays, we demonstrate that both crosslinks are formed DarE radical S-adenosylmethionine (SAM) O2-dependent manner. relevance observed activity...
Abstract Membrane contact sites (MCS) are subcellular regions where two organelles appose their membranes to exchange small molecules, including lipids. Structural information on how proteins form MCS is scarce. We designed an in vitro with and a pair of tethering suitable for cryo-tomography analysis. It includes VAP-A, ER transmembrane protein interacting myriad cytosolic proteins, oxysterol-binding (OSBP), lipid transfer that transports cholesterol from the trans Golgi network. show VAP-A...
A new series of 3-hydroxy-2-pyridine aldoxime compounds have been designed, synthesised and tested in vitro, silico, ex vivo as reactivators human acetylcholinesterase (hAChE) butyrylcholinesterase (hBChE) inhibited by organophosphates (OPs), for example, VX, sarin, cyclosarin, tabun, paraoxon. The reactivation rates three oximes (16-18) were determined to be greater than that 2-PAM comparable HI-6, two pyridinium aldoximes currently used the armies several countries. interactions important...
Acetylcholinesterase (AChE), a key enzyme in the central and peripheral nervous systems, is principal target of organophosphorus nerve agents. Quaternary oximes can regenerate AChE activity by displacing phosphyl group agent from active site, but they are poorly distributed system. A promising reactivator based on tetrahydroacridine linked to nonquaternary oxime also an undesired submicromolar reversible inhibitor AChE. X-ray structures molecular docking indicate that structural modification...
X-ray radiation induces two main effects at metal centres contained in protein crystals: radiation-induced reduction and radiolysis a resulting decrease occupancy. In blue multicopper oxidases (BMCOs), the geometry of active metal-to-ligand distances change depending on oxidation states Cu atoms, suggesting that these alterations are catalytically relevant to binding, activation O(2). this work, X-ray-determined three-dimensional structure laccase from basidiomycete Coriolopsis gallica (Cg...
The rate of radiation damage to macromolecular crystals at both room temperature and 100 K has previously been shown be reduced by the use certain radical scavengers. Here effects sodium nitrate, an electron scavenger, are investigated K. For nitrate a concentration 0.5 M in chicken egg-white lysozyme crystals, dose tolerance is increased factor two as judged from global parameters, no specific structural disulfide bonds seen until greatly excess (more than five) value which appears density...
Abstract The development of polyphenols as drugs for Alzheimer’s disease (AD) is thwarted by their meagre brain availability due to instability and poor druglikeness. Here we describe the successful stable, druglike polyphenolic analogues current AD drug rivastigmine, that have high apparent blood-brain barrier permeabilities multifunctional properties treatment. compounds inhibit cholinesterases amyloid beta (Aβ) fibrillation, protect against Aβ 42 -induced toxicity in vitro, demonstrate...
Abstract Reversibly photoswitchable fluorescent proteins are essential markers for advanced biological imaging, and optimization of their photophysical properties underlies improved performance novel applications. Here we establish a link between photoswitching contrast, one the key parameters that dictate achievable resolution in nanoscopy applications, chromophore conformation non‐fluorescent state rsEGFP2, widely employed label REversible Saturable OpticaL Fluorescence Transitions...
Ribosome biogenesis is orchestrated by the action of several accessory factors that provide time and directionality to process. One such factor GTPase EFL1 involved in cytoplasmic maturation ribosomal 60S subunit. SBDS, protein mutated Shwachman-Diamond syndrome (SBDS), release anti-association eIF6 from surface subunit 60S. Here we report a kinetic analysis fluorescent guanine nucleotides binding alone presence SBDS using fluorescence stopped-flow spectroscopy. Binding kinetics both GDP GTP...
Phytochromes are bilin-containing photoreceptors that typically sensitive to the red/far-red region of visible spectrum. Recently, phytochromes from certain eukaryotic algae have become attractive targets for optogenetic applications because their unique ability respond multiple wavelengths light. Herein, a combination time-resolved spectroscopy and structural approaches across picosecond second timescales been used map photochemical mechanisms changes in this atypical group phytochromes....
Acetylcholinesterase (AChE) inhibitors (AChEIs) still remain the leading therapeutic options for symptomatic treatment of cognitive deficits associated with mild-to-moderate Alzheimer's disease. The search new AChEIs benefits from well-established knowledge molecular interactions selective AChEIs, such as donepezil and related dual binding site inhibitors. Starting a previously disclosed coumarin-based inhibitor (±)-cis-1, active racemate in nanomolar range toward AChE, we proceeded on...
SdsA, a sodium dodecyl sulfate hydrolase, from Pseudomonas aeruginosa was crystallized in three different crystal polymorphs and their three-dimensional structure determined. The present packing habits. One of the suggests existence tetramer, an oligomeric state not observed previously, while remaining two obstructs active site entrance but stabilizes flexible regions protein. Nonconventional crystallization methods that minimize convection, such as counterdiffusion polyvinyl alcohol gel...
Abstract Endosomal sorting complexes required for transport-III (ESCRT-III) are thought to assemble in vivo inside membrane structures with a negative Gaussian curvature. How shape influences ESCRT-III polymerization and conversely how polymers membranes is still unclear. Here, we used human core proteins, CHMP4B, CHMP2A, CHMP2B CHMP3 address this issue vitro by combining nanotube pulling experiments, cryo-electron microscopy, tomography high-speed AFM. We show that CHMP4B filaments bind...
Abstract Reversibly photoswitchable fluorescent proteins are essential markers for advanced biological imaging, and optimization of their photophysical properties underlies improved performance novel applications. Here we establish a link between photoswitching contrast, key parameter that largely dictates the achievable resolution in nanoscopy applications, chromophore conformation non-fluorescent state rsEGFP2, widely employed label REversible Saturable OpticaL Fluorescence Transitions...
Ribosome biogenesis is closely linked to the cell growth and proliferation.Dysregulation of this process causes several diseases collectively known as ribosomopathies.One them Shwachman-Diamond Syndrome, SBDS protein mutated in disease participates with EFL1 cytoplasmic maturation 60S subunit.Recently, we have shown that interaction resulted a decrease Michaelis-Menten constant (K M ) for GTP thus acts GEF (1).Subsequent studies demonstrated debilitates GDP without altering (2).The alone or...