A5013129078- Nicotinic Acetylcholine Receptors Study
- Receptor Mechanisms and Signaling
- Ion channel regulation and function
- Cholinesterase and Neurodegenerative Diseases
- Antimicrobial Peptides and Activities
- Computational Drug Discovery Methods
- Plant-based Medicinal Research
- Prostate Cancer Treatment and Research
- Peroxisome Proliferator-Activated Receptors
- Synthesis and Biological Evaluation
- Click Chemistry and Applications
- Neuroscience and Neuropharmacology Research
- Monoclonal and Polyclonal Antibodies Research
- Chemical Synthesis and Analysis
- Crystallography and molecular interactions
- Photoreceptor and optogenetics research
- Chemical synthesis and alkaloids
- Molecular Junctions and Nanostructures
- Caveolin-1 and cellular processes
- Glycosylation and Glycoproteins Research
- Analytical Chemistry and Sensors
- bioluminescence and chemiluminescence research
- Advanced biosensing and bioanalysis techniques
- 14-3-3 protein interactions
- Protein Tyrosine Phosphatases
Université Paris Cité
2023-2024
Institut Pasteur
2013-2024
Centre National de la Recherche Scientifique
2013-2024
Nicolaus Copernicus University
2024
University of Montana
2009-2014
University of California, San Diego
2009-2014
Physical Sciences (United States)
2012
Scripps Research Institute
2012
Significance We describe the X-ray structures of same pentameric ligand-gated ion channel (pLGIC) in both its liganded or ligand-free conformations. This provides molecular basis for understanding opening and closing (gating mechanism) these key players fast transmission chemical signals at synapses. As described with classical allosteric proteins, tertiary changes subunits are linked together through quaternary constraint by a marked reorganization interfaces between associated binding...
Nicotinic acetylcholine receptors (nAChRs), which are responsible for mediating key physiological functions, ubiquitous in the central and peripheral nervous systems. As members of Cys loop ligand-gated ion channel family, neuronal nAChRs pentameric, composed various permutations α (α2 to α10) β (β2 β4) subunits forming functional heteromeric or homomeric receptors. Diversity nAChR subunit composition complicates development selective ligands specific subtypes, since five binding sites...
Determining the structure of ligand-binding domain nicotinic acetylcholine receptor (nAChR) has been a long standing goal in design selective drugs useful implicated diseases for this prevalent family. Acetylcholine-binding proteins have proven to be valuable surrogates with structural similarity and sequence identity extracellular receptor, yet these soluble their unique features do not serve as exact replicates nAChRs interest. Here we systematically modify toward homomeric human α7 nAChR....
We present a cell based system and experimental approach to characterize agonist antagonist selectivity for ligand-gated ion channels (LGIC) by developing sensor cells stably expressing Ca2+ permeable LGIC genetically encoded Förster (or fluorescence) resonance energy transfer (FRET)-based calcium sensor. In particular, we describe separate lines with human α7 α4β2 nicotinic acetylcholine receptors, mouse 5-HT3A serotonin receptors chimera of α7/mouse receptors. Complete...
Significance Pentameric ligand-gated ion channels (pLGICs) mediate fast signal transduction in animal nerve cells through neurotransmitters. Mutation of some these receptors the brain causes severe nervous system diseases. The high sequence diversity prokaryotic makes them unique model systems to understand evolutionary conservation gating and sensitivity allosteric modulators. We present 2.3 Å X-ray structure a pLGIC (sTeLIC) from gammaproteobacteria that is activated at alkaline pH. pH 8.0...
The Gloeobacter violaceus ligand-gated ion channel (GLIC) has been extensively studied by X-ray crystallography and other biophysical techniques. This provided key insights into the general gating mechanism of pentameric (pLGIC) signal transduction. However, GLIC is activated lowering pH location its putative proton activation site(s) still remain(s) unknown. To this end, every Asp, Glu, His residue was mutated individually or in combination investigated electrophysiology. In addition to...
Using the bacterial proton-activated pentameric receptor-channel Gloeobacter violaceus ligand-gated ion channel (GLIC): (1) We characterize saturated, mono-carboxylates as negative modulators of GLIC (as previously shown for crotonate; Alqazzaz et al., Biochemistry, 2016, 55, 5947). Butyrate and crotonate have indistinguishable properties regarding modulation wt GLIC. (2) identify a locus in pre-β5 strand (Loop Ω) whose mutation inverses effect mono-carboxylate from to positive allosteric...
The α7 nicotinic acetylcholine receptor (nAChR), a potential drug target for treating cognitive disorders, mediates communication between neuronal and non-neuronal cells. Although many competitive antagonists, agonists, partial-agonists have been found synthesized, they not led to effective therapeutic treatments. In this context, small molecules acting as positive allosteric modulators binding outside the orthosteric, acetylcholine, site attracted considerable interest. Two single-domain...
The acetylcholine-binding proteins (AChBPs), which serve as structural surrogates for the extracellular domain of nicotinic acetylcholine receptors (nAChRs), were used reaction templates in situ click-chemistry reactions to generate a congeneric series triazoles from azide and alkyne building blocks. catalysis azide-alkyne cycloaddition at dynamic subunit interface facilitated synthesis potentially selective compounds nAChRs. We investigated compound sets generated with soluble AChBP through...
Gloeobacter violaceus ligand-gated ion channel (GLIC) is a prokaryotic orthologue of brain pentameric neurotransmitter receptors. Using whole-cell patch-clamp electrophysiology in host cell line, we show that short-chain dicarboxylate compounds are positive modulators pHo 5-evoked GLIC activity, with rank order action fumarate > succinate malonate glutarate. Potentiation by depends on intracellular pH, mainly as result strong decrease the current when pH decreases. The modulating effect also...
Pentameric ligand-gated ion channels provide rapid chemical-electrical signal transmission between cells in the central and peripheral nervous system. Their dysfunction is associated with many system disorders. They are composed of five identical (homomeric receptors) or homologous (heteromeric subunits. VHH nanobodies, single-chain antibodies, variable domain, VH
Abstract The bacterial model GLIC remains one of the best known among pentameric ligand-gated ion channels (pLGICs), regarding their structure. is activated at low extracellular pH, but no agonist compound known. Van Renterghem et al . (2023) showed that short-chain di-carboxylates potentiate activity, with strict dependence on two carboxylate binding pockets, previously characterized by crystallography (Sauguet ., 2013, Fourati 2015, 2020). An “in series” was proposed, inter-subunit pocket...
The α7 nicotinic acetylcholine receptor (nAChR), which is a member of pentameric ligand‐gated ion channel receptors, novel candidate target for treatment Alzheimer’s disease, schizophrenia, other CNS disorders, peripheral pain and inflammation. Proteins homologous to the extracellular domain nAChRs from Aplysia californica (Ac) Lymnaea stagnalis (Ls)acetylcholine binding proteins (AChBPs) are expressed purified as templates drug design, x‐ray crystallography, affinity assays. Based on poses...