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This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact
Science: general issues --- Pharmacology --- α-conotoxins --- Three-finger Ly6 proteins --- nicotinic receptors --- Cys-loop receptors --- Voltage-gated ion channels --- receptor complexes --- drug design
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This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact
α-conotoxins --- Three-finger Ly6 proteins --- nicotinic receptors --- Cys-loop receptors --- Voltage-gated ion channels --- receptor complexes --- drug design
Choose an application
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This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact
Science: general issues --- Pharmacology --- α-conotoxins --- Three-finger Ly6 proteins --- nicotinic receptors --- Cys-loop receptors --- Voltage-gated ion channels --- receptor complexes --- drug design --- α-conotoxins --- Three-finger Ly6 proteins --- nicotinic receptors --- Cys-loop receptors --- Voltage-gated ion channels --- receptor complexes --- drug design
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The α7 nicotinic acetylcholine receptor (nAChR) is an excitatory ligand-gated ion channel activated by the neurotransmitter acetylcholine. Dysfunction of the cholinergic system has been shown to be involved in Alzheimer’s disease and schizophrenia. Both conditions are characterized by decreased α7 nAChR expression in key brain areas involved in cognition, including the hippocampus and cortex. A potential novel therapeutic strategy to improve cognition is positive-allosteric modulation of the α7 nAChR. This implies that a positive-allosteric modulator (PAM) binds to a different site of the receptor than acetylcholine, thereby enhancing α7 nAChR function when acetylcholine is present. The PAM will be developed by structure-based drug design. However, the structure of the human α7 nAChR at atomic resolution is currently unavailable. Therefore, a humanized chimaeric receptor composed of human α7 nAChR and Lymnaea stagnalis acetylcholine-binding protein sequences (α7 AChBP) was used as a surrogate for the extracellular domain of the human α7 nAChR. In order to improve the model, sharing 71 % sequence similarity with the human α7 nAChR, seven additional humanizing mutations were introduced in the vestibule pocket. This pocket corresponds to a site involved in positive-allosteric modulation of ELIC by benzodiazepines. Previously, several allosteric modulators binding in the vestibule pocket of α7 AChBP, have been identified. In this study, the X-ray structure of α7 AChBP, with seven additional humanizing mutations in the vestibule pocket, was determined. Afterwards, fragment library screening at the XChem fragment screening facility of the Diamond was performed and the structure was solved in presence of different fragments.
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Cys-loop receptoren of pentamere ligand-geactiveerde ionenkanalen zijn verantwoordelijk voor snelle exciterende en inhiberende neurotransmissie in het perifere en centrale zenuwstelsel. Dysfunctie van deze receptoren speelt een belangrijke rol in verscheidene neurologische aandoeningen en bovendien vormen pLGICs een belangrijk klinisch doelwit voor een aantal frequent voorgeschreven geneesmiddelen. Een betere kennis van structuur, neurotransmitter modulatie en ligand herkenning zou leiden tot verbeterde pathofysiologische inzichten en zou een rationele structuur-gebaseerde geneesmiddelenontwikkeling ondersteunen. Structurele en functionele studies openen dus deuren naar selectievere en effectievere geneesmiddelen of behandelingen. Deze studie is gericht op het karakteriseren van de thermische stabiliteit van een invertebrate Cys-loop receptor homoloog genaamd Alpo 4 uit Alvinella pompejana. Alpo 4 is een kation-selectief kanaal. Het deelt een 25,89% sequentie identiteit met de humane 7 nicotine acetylcholine receptor en 24,67% sequentie identiteit met de 5-HT3A receptor. Additie van steroïde-afgeleide detergenten CHAPS en CHAPSO leidde tot een verhoogde thermische stabiliteit van Alpo 4 eGFP ic. Uitgaande van dit experiment werd Alpo 4 wild type opgezuiverd met CHAPS als additief, wat leidde tot een succesvolle opzuivering met verhoogde opbrengst en goed gelfiltratieprofiel. Met het opgezuiverd eiwit werden kristallisatiepogingen gedaan.
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