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https://www.readbyqxmd.com/read/28446950/analgesic-effect-of-17%C3%AE-estradiol-on-nucleus-paragigantocellularis-lateralis-of-male-rats-mediated-via-gabaa-receptors
#1
Roghaieh Khakpay, Maryam Azaddar, Fatemeh Khakpay, Homeira Hatami Nemati
INTRODUCTION: Beside its autonomic functions, the nucleus paragigantocellularis lateralis (LPGi) is involved in the descending pain modulation. 17β-Estradiol is a neuroactive steroid found in several brain areas such as LPGi. Intra-LPGi microinjection of 17β-estradiol can elicit the analgesic responses. 17β-Estradiol modulates nociception by binding to estrogenic receptors as well as allosteric interaction with other membrane-bound receptors like GABAA receptors. This study aimed to examine the role of GABAA receptors in the pain modulating effect of intra-LPGi injection of 17β-estradiol...
January 2017: Basic and Clinical Neuroscience
https://www.readbyqxmd.com/read/28446611/unraveling-amino-acid-residues-critical-for-allosteric-potentiation-of-%C3%AE-4-3-%C3%AE-2-2-type-nicotinic-acetylcholine-receptor-responses
#2
Ze-Jun Wang, Farah Deba, Tasnim S Mohamed, David C Chiara, Kara Ramos, Ayman K Hamouda
Neuronal nicotinic acetylcholine receptors (nAChRs) are promising drug targets to manage several neurological disorders and nicotine addiction. Growing evidence indicates that positive allosteric modulators (PAMs) of nAChRs improve pharmacological specificity by binding to unique sites present only in a subpopulation of nAChRs. Furthermore, nAChR PAMs such as NS9283 and CMPI have been shown to potentiate responses of (α4)3(β2)2 but not (α4)2(β2)3 nAChR isoforms. This selective potentiation underlines that the α4:α4 interface, which is present only in the (α4)3(β2)2 nAChR, is an important and promising drug target...
April 26, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28446243/targeting-metabotropic-glutamate-receptors-for-novel-treatments-of-schizophrenia
#3
REVIEW
James Maksymetz, Sean P Moran, P Jeffrey Conn
Support for the N-methyl-D-aspartate receptor (NMDAR) hypofunction hypothesis of schizophrenia has led to increasing focus on restoring proper glutamatergic signaling as an approach for treatment of this devastating disease. The ability of metabotropic glutamate (mGlu) receptors to modulate glutamatergic neurotransmission has thus attracted considerable attention for the development of novel antipsychotics. Consisting of eight subtypes classified into three groups based on sequence homology, signal transduction, and pharmacology, the mGlu receptors provide a wide range of targets to modulate NMDAR function as well as glutamate release...
April 26, 2017: Molecular Brain
https://www.readbyqxmd.com/read/28445750/effect-of-phosphorylation-on-a-human-like-osteopontin-peptide
#4
Samuel Lenton, Marco Grimaldo, Felix Roosen-Runge, Frank Schreiber, Tommy Nylander, Roger Clegg, Carl Holt, Michael Härtlein, Victoria García Sakai, Tilo Seydel, Susana C Marujo Teixeira
The last decade established that the dynamic properties of the phosphoproteome are central to function and its modulation. The temporal dimension of phosphorylation effects remains nonetheless poorly understood, particularly for intrinsically disordered proteins. Osteopontin, selected for this study due to its key role in biomineralization, is expressed in many species and tissues to play a range of distinct roles. A notable property of highly phosphorylated isoforms of osteopontin is their ability to sequester nanoclusters of calcium phosphate to form a core-shell structure, in a fluid that is supersaturated but stable...
April 25, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28445455/structural-insight-into-allosteric-modulation-of-protease-activated-receptor-2
#5
Robert K Y Cheng, Cédric Fiez-Vandal, Oliver Schlenker, Karl Edman, Birte Aggeler, Dean G Brown, Giles A Brown, Robert M Cooke, Christoph E Dumelin, Andrew S Doré, Stefan Geschwindner, Christoph Grebner, Nils-Olov Hermansson, Ali Jazayeri, Patrik Johansson, Louis Leong, Rudi Prihandoko, Mathieu Rappas, Holly Soutter, Arjan Snijder, Linda Sundström, Benjamin Tehan, Peter Thornton, Dawn Troast, Giselle Wiggin, Andrei Zhukov, Fiona H Marshall, Niek Dekker
Protease-activated receptors (PARs) are a family of G-protein-coupled receptors (GPCRs) that are irreversibly activated by proteolytic cleavage of the N terminus, which unmasks a tethered peptide ligand that binds and activates the transmembrane receptor domain, eliciting a cellular cascade in response to inflammatory signals and other stimuli. PARs are implicated in a wide range of diseases, such as cancer and inflammation. PARs have been the subject of major pharmaceutical research efforts but the discovery of small-molecule antagonists that effectively bind them has proved challenging...
April 26, 2017: Nature
https://www.readbyqxmd.com/read/28445029/nhs-esters-as-versatile-reactivity-based-probes-for-mapping-proteome-wide-ligandable-hotspots
#6
Carl C Ward, Jordan I Kleinman, Daniel K Nomura
Most of the proteome is considered undruggable oftentimes hindering translational efforts for drug discovery. Identifying previously unknown druggable hotspots in proteins would enable strategies for pharmacologically interrogating these sites with small-molecules. Activity-based protein profiling (ABPP) has arisen as a powerful chemoproteomic strategy that uses reactivity-based chemical probes to map reactive, functional, and ligandable hotspots in complex proteomes, which has enabled inhibitor discovery against various therapeutic protein targets...
April 26, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28443330/mechanisms-by-which-salt-concentration-moderates-the-dynamics-of-human-serum-transferrin
#7
Haleh Abdizadeh, Ali Rana Atilgan, Canan Atilgan
The dynamical and thermodynamic behavior of human transferrin (hTf) protein in saline aqueous solution of various concentrations is studied. hTf is an essential transport protein circulating iron in the blood and delivering it to tissues. It displays highly pH dependent cooperativity between the two lobes each carrying an iron, and forms a tight complex with the receptor during endocytosis, eventually recycled to the serum after iron release. Molecular dynamics simulations are used to investigate the effects of the amount of salt on protein conformation and dynamics to analyze the structure-function relationship in free hTf at serum pH...
April 26, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28442369/further-evaluation-of-the-potential-anxiolytic-activity-of-imidazo-1-5-a-1-4-diazepin-agents-selective-for-%C3%AE-2-3-containing-gabaa-receptors
#8
J M Witkin, R Cerne, M Wakulchik, J S, S D Gleason, T M Jones, G Li, L A Arnold, Jun-Xu Li, J M Schkeryantz, K R Methuku, J M Cook, M M Poe
Positive allosteric modulators of GABAA receptors transduce a host of beneficial effects including anxiolytic actions. We have recently shown that bioavailability and anxiolytic-like activity can be improved by eliminating the ester functionality in imidazo[1,5-a][1,4]diazepines. In the present series of experiments, we further substantiate the value of heterocyle replacement of the ester for potential treatment of anxiety. None of the three esters was active in a Vogel conflict test in rats that detects anxiolytic drugs like diazepam...
April 22, 2017: Pharmacology, Biochemistry, and Behavior
https://www.readbyqxmd.com/read/28442348/upregulation-of-neurotrophins-by-s-47445-a-novel-positive-allosteric-modulator-of-ampa-receptors-in-aged-rats
#9
Francesca Calabrese, Elisa Savino, Elisabeth Mocaer, Sylvie Bretin, Giorgio Racagni, Marco A Riva
At molecular levels, it has been shown that aging is associated with alterations in neuroplastic mechanisms. In this study, it was examined if the altered expression of neurotrophins observed in aged rats could be corrected by a chronic treatment with S 47445 (1-3-10mg/kg, p.o.), a novel selective positive allosteric modulator of the AMPA receptors. Both the mRNA and the protein levels of the neurotrophins Bdnf, NT-3 and Ngf were specifically measured in the prefrontal cortex and hippocampus (ventral and dorsal) of aged rats...
April 22, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28442253/optimization-of-m4-positive-allosteric-modulators-pams-the-discovery-of-vu0476406-a-non-human-primate-in-vivo-tool-compound-for-translational-pharmacology
#10
Bruce J Melancon, Michael R Wood, Meredith J Noetzel, Kellie D Nance, Eileen M Engelberg, Changho Han, Atin Lamsal, Sichen Chang, Hyekyung P Cho, Frank W Byers, Michael Bubser, Carrie K Jones, Colleen M Niswender, Michael W Wood, Darren W Engers, Dedong Wu, Nicholas J Brandon, Mark E Duggan, P Jeffrey Conn, Thomas M Bridges, Craig W Lindsley
This letter describes the further chemical optimization of the 5-amino-thieno[2,3-c]pyridazine series (VU0467154/VU0467485) of M4 positive allosteric modulators (PAMs), developed via iterative parallel synthesis, culminating in the discovery of the non-human primate (NHP) in vivo tool compound, VU0476406 (8p). VU0476406 is an important in vivo tool compound to enable translation of pharmacodynamics from rodent to NHP, and while data related to a Parkinson's disease model has been reported with 8p, this is the first disclosure of the optimization and discovery of VU0476406, as well as detailed pharmacology and DMPK properties...
April 13, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28440659/alleviation-of-multiple-asthmatic-pathologic-features-with-orally-available-and-subtype-selective-gabaa-receptor-modulators
#11
Gloria S Forkuo, Amanda N Nieman, Nina Y Yuan, Revathi Kodali, Olivia B Yu, Nicolas M Zahn, Rajwana Jahan, Guanguan Li, Michael Rajesh Stephen, Margaret L Guthrie, Michael M Poe, Benjamin D Hartzler, Ted William Harris, Gene T Yocum, Charles W Emala, Douglas A Steeber, Douglas C Stafford, James M Cook, Leggy A Arnold
We describe pharmacokinetic and pharmacodynamic properties of two novel oral drug candidates for asthma. Phenolic α4β3γ2 GABAAR selective compound 1 and acidic α5β3γ2 selective GABAAR positive allosteric modulator compound 2 relaxed airway smooth muscle ex vivo and attenuated airway hyperresponsiveness (AHR) in a murine model of asthma. Importantly, compound 2 relaxed acetylcholine contracted human tracheal airway smooth muscle strips. Oral treatment of compound 1 and 2 decreased eosinophils in bronchoalveolar lavage fluid in ovalbumin sensitized and challenged mice, thus exhibiting anti-inflammatory properties...
April 25, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28440616/discovery-and-characterization-of-a-eukaryotic-initiation-factor-4a-3-selective-inhibitor-that-suppresses-nonsense-mediated-mrna-decay
#12
Misa Iwatani-Yoshihara, Masahiro Ito, Yoshihiro Ishibashi, Hideyuki Oki, Toshio Tanaka, Daisuke Morishita, Takashi Ito, Hiromichi Kimura, Yasuhiro Imaeda, Samuel A Aparicio, Atsushi Nakanishi, Tomohiro Kawamoto
Eukaryotic initiation factor 4A-3 (eIF4A3) is an Asp-Glu-Ala-Asp (DEAD) box-family adenosine triphosphate (ATP)-dependent RNA helicase. Subtypes eIF4A1 and eIF4A2 are required for translation initiation, but eIF4A3 participates in the exon junction complex (EJC) and functions in RNA metabolism including nonsense-mediated RNA decay (NMD). No small molecules for NMD inhibition via selective inhibition of eIF4A3 have been discovered. Here we identified allosteric eIF4A3 inhibitors from a high-throughput screening campaign...
April 25, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28438838/allosteric-mechanism-of-action-of-the-therapeutic-anti-ige-antibody-omalizumab
#13
Anna M Davies, Elizabeth G Allan, Anthony H Keeble, Jean Delgado, Benjamin P Cossins, Alkistis N Mitropoulou, Marie O Y Pang, Tom Ceska, Andrew J Beavil, Graham Craggs, Marta Westwood, Alistair J Henry, James M McDonnell, Brian J Sutton
Immunoglobulin E and its interactions with receptors FcϵRI and CD23 play a central role in allergic disease. Omalizumab, a clinically-approved therapeutic antibody, inhibits the interaction between IgE and FcϵRI, preventing mast cell and basophil activation, and blocks IgE binding to CD23 on B cells and antigen-presenting cells. We solved the crystal structure of the complex between an omalizumab-derived Fab and IgE-Fc, with one Fab bound to each Cϵ3 domain. Free IgE-Fc adopts an acutely bent structure, but in the complex it is only partially bent, with large-scale conformational changes in the Cϵ3 domains that inhibit the interaction with FcϵRI...
April 24, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28437106/allosteric-targeting-of-the-fanconi-anemia-ubiquitin-conjugating-enzyme-ube2t-by-fragment-screening
#14
Francesca E Morreale, Alessio Bortoluzzi, Viduth K Chaugule, Connor Arkinson, Helen Walden, Alessio Ciulli
Ube2T is the E2 ubiquitin-conjugating enzyme of the Fanconi anemia DNA repair pathway and it's overexpressed in several cancers, representing an attractive target for the development of inhibitors. Despite the extensive efforts in targeting the ubiquitin system, very few E2 binders have currently been discovered. Herein we report the identification of a new allosteric pocket on Ube2T through a fragment screening using biophysical methods. Several fragments binding to this site inhibit ubiquitin conjugation in vitro...
April 24, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28436707/samhd1-protects-cancer-cells-from-various-nucleoside-based-antimetabolites
#15
Nikolas Herold, Sean G Rudd, Kumar Sanjiv, Juliane Kutzner, Julia Bladh, Cynthia B J Paulin, Thomas Helleday, J I Henter, Torsten Schaller
Recently, we demonstrated that sterile alpha motif and HD domain containing protein 1 (SAMHD1) is a major barrier in acute myelogenous leukemic (AML) cells to the cytotoxicity of cytarabine (ara-C), the most important drug in AML treatment. Ara-C is intracellularly converted by the canonical dNTP synthesis pathway to ara-CTP, which serves as a substrate but not an allosteric activator of SAMHD1. Using an AML mouse model, we show here that wild type but not catalytically inactive SAMHD1 reduces ara-C treatment efficacy in vivo...
April 24, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28436443/curcumol-allosterically-modulates-gaba-a-receptors-in-a-manner-distinct-from-benzodiazepines
#16
Yan-Mei Liu, Hui-Ran Fan, Jing Ding, Chen Huang, Shining Deng, Tailin Zhu, Tian-Le Xu, Wei-Hong Ge, Wei-Guang Li, Fei Li
Inhibitory A type γ-aminobutyric acid receptors (GABAARs) play a pivotal role in orchestrating various brain functions and represent an important molecular target in neurological and psychiatric diseases, necessitating the need for the discovery and development of novel modulators. Here, we show that a natural compound curcumol, acts as an allosteric enhancer of GABAARs in a manner distinct from benzodiazepines. Curcumol markedly facilitated GABA-activated currents and shifted the GABA concentration-response curve to the left in cultured hippocampal neurons...
April 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28435869/a-dynamic-hydrophobic-core-orchestrates-allostery-in-protein-kinases
#17
Jonggul Kim, Lalima G Ahuja, Fa-An Chao, Youlin Xia, Christopher L McClendon, Alexandr P Kornev, Susan S Taylor, Gianluigi Veglia
Eukaryotic protein kinases (EPKs) constitute a class of allosteric switches that mediate a myriad of signaling events. It has been postulated that EPKs' active and inactive states depend on the structural architecture of their hydrophobic cores, organized around two highly conserved spines: C-spine and R-spine. How the spines orchestrate the transition of the enzyme between catalytically uncommitted and committed states remains elusive. Using relaxation dispersion nuclear magnetic resonance spectroscopy, we found that the hydrophobic core of the catalytic subunit of protein kinase A, a prototypical and ubiquitous EPK, moves synchronously to poise the C subunit for catalysis in response to binding adenosine 5'-triphosphate...
April 2017: Science Advances
https://www.readbyqxmd.com/read/28434782/dimeric-isoxazolyl-1-4-dihydropyridines-have-enhanced-binding-at-the-multi-drug-resistance-transporter
#18
Scott A Steiger, Chun Li, Donald S Backos, Philip Reigan, N R Natale
A series of dimeric isoxazolyl-1,4-dihydropyridines (IDHPs) were prepared by click chemistry and examined for their ability to bind the multi-drug resistance transporter (MDR-1), a member of the ATP-binding cassette superfamily (ABC). Eight compounds in the present study exhibited single digit micromolar binding to this efflux transporter. One monomeric IDHP m-Br-1c, possessed submicromolar binding of 510nM at MDR-1. Three of the dimeric IDHPs possessed <1.5µM activity, and 4b and 4c were observed to have superior binding selectivity compared to their corresponding monomers verses the voltage gated calcium channel (VGCC)...
April 8, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28432788/structure-of-fam20a-reveals-a-pseudokinase-featuring-unique-disulfide-pattern-and-inverted-atp-binding
#19
Jixin Cui, Qinyu Zhu, Hui Zhang, Michael A Cianfrocco, Andres E Leschziner, Jack E Dixon, Junyu Xiao
Mutations in FAM20A cause tooth enamel defects known as Amelogenesis Imperfecta (AI) and renal calcification. We previously showed that Fam20A is a secretory pathway pseudokinase and allosterically activates the physiological casein kinase Fam20C to phosphorylate secreted proteins important for biomineralization (Cui et al., 2015). Here we report the nucleotide-free and ATP-bound structures of Fam20A. Fam20A exhibits a distinct disulfide bond pattern mediated by a unique insertion region. Loss of this insertion due to abnormal mRNA splicing interferes with the structure and function of Fam20A, resulting in AI...
April 22, 2017: ELife
https://www.readbyqxmd.com/read/28432493/effect-of-pharmacological-modulation-of-activity-of-metabotropic-glutamate-receptors-on-their-gene-expression-after-excitotoxic-damage-in-hippocampal-neurons
#20
E V Pershina, M V Kapralova, V I Arkhipov
Microinjection of kainic acid into rat hippocampus causes excitotoxic neuronal damage predominantly in the CA3 and CA1 fields. These lesions can be significantly reduced by simultaneous administration of MPEP, a negative allosteric modulator of type 5 metabotropic glutamate receptors, and LY354740, an agonist of type 2 metabotropic glutamate receptors. The decrease in neuronal death in the hippocampus during pharmacological modulation was paralleled by adaptive changes in gene expression. In the hippocampus, gene expression of type 5 postsynaptic metabotropic glutamate receptor was close to the control level, and in the frontal cortex expression of the gene of α1-subunit of the GABAA receptor returned to normal...
April 22, 2017: Bulletin of Experimental Biology and Medicine
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