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https://www.readbyqxmd.com/read/28719589/an-excited-state-underlies-gene-regulation-of-a-transcriptional-riboswitch
#1
Bo Zhao, Sharon L Guffy, Benfeard Williams, Qi Zhang
Riboswitches control gene expression through ligand-dependent structural rearrangements of the sensing aptamer domain. However, we found that the Bacillus cereus fluoride riboswitch aptamer adopts identical tertiary structures in solution with and without ligand. Using chemical-exchange saturation transfer (CEST) NMR spectroscopy, we revealed that the structured ligand-free aptamer transiently accesses a low-populated (∼1%) and short-lived (∼3 ms) excited conformational state that unravels a conserved 'linchpin' base pair to signal transcription termination...
July 17, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28719234/the-in-vivo-effects-of-the-cb1-positive-allosteric-modulator-gat229-on-intraocular-pressure-in-ocular-normotensive-and-hypertensive-mice
#2
Elizabeth A Cairns, Anna-Maria Szczesniak, Alex J Straiker, Pushkar M Kulkarni, Roger G Pertwee, Ganesh A Thakur, William H Baldridge, Melanie E M Kelly
PURPOSE: Orthosteric cannabinoid receptor 1 (CB1) activation leads to decreases in intraocular pressure (IOP). However, use of orthosteric CB1 agonists chronically has several disadvantages, limiting their usefulness as clinically relevant drugs. Allosteric modulators interact with topographically distinct sites to orthosteric ligands and may be useful to circumvent some of these disadvantages. The purpose of this study was to investigate the effects of the novel CB1-positive allosteric modulator (PAM) GAT229 on IOP...
July 18, 2017: Journal of Ocular Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28718281/long-distance-modulation-of-disorder-to-order-in-protein-allostery
#3
Jingheng Wang, Gregory S Custer, Dorothy Beckett, Silvina Matysiak
Elucidation of the molecular details of allosteric communication between distant sites in a protein is key to understanding and manipulating many biological regulatory processes. Although protein disorder is acknowledged to play an important thermodynamic role in allostery, the molecular mechanisms by which this disorder is harnessed for long distance communication are known for a limited number of systems. Transcription repression by the E. coli biotin repressor, BirA, is allosterically activated by binding of the small molecule effector biotinoyl-5'-AMP...
July 18, 2017: Biochemistry
https://www.readbyqxmd.com/read/28717969/decreasing-the-expression-of-gabaa-%C3%AE-5-subunit-containing-receptors-partially-improves-cognitive-electrophysiological-and-morphological-hippocampal-defects-in-the-ts65dn-model-of-down-syndrome
#4
Verónica Vidal, Susana García-Cerro, Paula Martínez, Andrea Corrales, Sara Lantigua, Rebeca Vidal, Noemí Rueda, Laurence Ozmen, Maria-Clemencia Hernández, Carmen Martínez-Cué
Trisomy 21 or Down syndrome (DS) is the most common cause of intellectual disability of a genetic origin. The Ts65Dn (TS) mouse, which is the most commonly used and best-characterized mouse model of DS, displays many of the cognitive, neuromorphological, and biochemical anomalies that are found in the human condition. One of the mechanisms that have been proposed to be responsible for the cognitive deficits in this mouse model is impaired GABA-mediated inhibition. Because of the well-known modulatory role of GABAA α5 subunit-containing receptors in cognitive processes, these receptors are considered to be potential targets for improving the intellectual disability in DS...
July 17, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28717967/orexin-a-hypocretin-modulates-leptin-receptor-mediated-signaling-by-allosteric-modulations-mediated-by-the-ghrelin-ghs-r1a-receptor-in-hypothalamic-neurons
#5
Mireia Medrano, David Aguinaga, Irene Reyes-Resina, Enric I Canela, Josefa Mallol, Gemma Navarro, Rafael Franco
The hypothalamus is a key integrator of nutrient-seeking signals in the form of hormones and metabolites originated in both the central nervous system and the periphery. The main autocrine and paracrine target of orexinergic-related hormones such as leptin, orexin/hypocretin, and ghrelin are neuropeptide Y neurons located in the arcuate nucleus of the hypothalamus. The aim of this study was to investigate the expression and the molecular and functional relationships between leptin, orexin/hypocretin and ghrelin receptors...
July 17, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28717188/targeting-ptprz-inhibits-stem-cell-like-properties-and-tumorigenicity-in-glioblastoma-cells
#6
Akihiro Fujikawa, Hajime Sugawara, Taisaku Tanaka, Masahito Matsumoto, Kazuya Kuboyama, Ryoko Suzuki, Naomi Tanga, Atsuto Ogata, Makoto Masumura, Masaharu Noda
The R5 subfamily of receptor-type protein tyrosine phosphatases (RPTPs) comprises PTPRZ and PTPRG. A recent study on primary human glioblastomas suggested a close association between PTPRZ1 (human PTPRZ) expression and cancer stemness. However, the functional roles of PTPRZ activity in glioma stem cells have remained unclear. In the present study, we found that sphere-forming cells from the rat C6 and human U251 glioblastoma cell lines showed high expression levels of PTPRZ-B, the short receptor isoform of PTPRZ...
July 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28716664/advances-and-challenges-in-the-search-for-d2-and-d3-dopamine-receptor-selective-compounds
#7
REVIEW
Amy E Moritz, R Benjamin Free, David R Sibley
Compounds that target D2-like dopamine receptors (DRs) are currently used as therapeutics for several neuropsychiatric disorders including schizophrenia (antagonists) and Parkinson's disease (agonists). However, as the D2R and D3R subtypes are highly homologous, creating compounds with sufficient subtype-selectivity as well as drug-like properties for therapeutic use has proved challenging. This review summarizes the progress that has been made in developing D2R- or D3R-selective antagonists and agonists, and also describes the experimental conditions that need to be considered when determining the selectivity of a given compound, as apparent selectivity can vary widely depending on assay conditions...
July 14, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28715126/an-engineered-photoswitchable-mammalian-pyruvate-kinase
#8
Stefanie Gehrig, Jamie A Macpherson, Paul C Driscoll, Alastair Symon, Stephen R Martin, James I MacRae, Jens Kleinjung, Franca Fraternali, Dimitrios Anastasiou
Changes in allosteric regulation of glycolytic enzymes have been linked to metabolic reprogramming involved in cancer. Remarkably, allosteric mechanisms control enzyme function at significantly shorter time-scales compared to the long-term effects of metabolic reprogramming on cell proliferation. It remains unclear if and how the speed and reversibility afforded by rapid allosteric control of metabolic enzymes is important for cell proliferation. Tools that allow specific, dynamic modulation of enzymatic activities in mammalian cells would help address this question...
July 17, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28714871/signaling-within-allosteric-machines-signal-transmission-pathways-inside-g-protein-coupled-receptors
#9
REVIEW
Damian Bartuzi, Agnieszka A Kaczor, Dariusz Matosiuk
In recent years, our understanding of function of G protein-coupled receptors (GPCRs) has changed from a picture of simple signal relays, transmitting only a particular signal to a particular G protein heterotrimer, to versatile machines, capable of various responses to different stimuli and being modulated by various factors. Some recent reports provide not only the data on ligands/modulators and resultant signals induced by them, but also deeper insights into exact pathways of signal migration and mechanisms of signal transmission through receptor structure...
July 15, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28714505/the-antiproliferative-activity-of-di-2-pyridylketone-dithiocarbamate-is-partly-attributed-to-catalase-inhibition-detailing-the-interaction-by-spectroscopic-methods
#10
Cuiping Li, Youxun Liu, Yun Fu, Tengfei Huang, Lixia Kang, Changzheng Li
The bioactivity of drugs is attributed to their interaction with biological molecules, embodied in either their direct or indirect influence on enzyme activity and conformation. Di-2-pyridylketone hydrazine dithiocarbamate (DpdtC) exhibits significant antitumor activity in our preliminary study. We speculated that its activity may partly stem from enzyme inhibition due to strong metal chelating ability. To this end, we assessed its effect on catalase from erythrocytes and found evidence of inhibition, which was further confirmed by ROS determination in vivo...
July 17, 2017: Molecular BioSystems
https://www.readbyqxmd.com/read/28713569/kctd12-modulation-of-gaba-b-receptor-function
#11
Melody Li, Carol J Milligan, Haiyan Wang, Andrew Walker, Leonid Churilov, Andrew J Lawrence, Christopher A Reid, Seth C Hopkins, Steven Petrou
The molecular composition and functional diversity of native GABAB receptors (GABABR) are still poorly understood, thus hindering development of selective GABABR ligands. Potassium channel tetramerization domain-containing protein (KCTD) 12 is a GABABR auxiliary subunit and mouse KCTD12 can alter GABABR function. In this study, we sought to characterize the effects of human KCTD12 on GABABR kinetics and pharmacology, using an automated electrophysiological assay. Seizure susceptibility and ethanol consumption were also investigated in a KCTD12 knockout mouse model...
August 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28710390/conformational-transitions-of-the-pituitary-adenylate-cyclase-activating-polypeptide-receptor-a-human-class-b-gpcr
#12
Chenyi Liao, Xiaochuan Zhao, Matthias Brewer, Victor May, Jianing Li
The G protein-coupled pituitary adenylate cyclase-activating polypeptide receptor (PAC1R) is a potential therapeutic target for endocrine, metabolic and stress-related disorders. However, many questions regarding the protein structure and dynamics of PAC1R remain largely unanswered. Using microsecond-long simulations, we examined the open and closed PAC1R conformations interconnected within an ensemble of transitional states. The open-to-closed transition can be initiated by "unzipping" the extracellular domain and the transmembrane domain, mediated by a unique segment within the β3-β4 loop...
July 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28710372/phthalide-derivatives-from-angelica-sinensis-decrease-hemoglobin-oxygen-affinity-a-new-allosteric-modulating-mechanism-and-potential-use-as-2-3-bpg-functional-substitutes
#13
Wei-Ren Chen, Youqing Yu, Muhammad Zulfajri, Ping-Cheng Lin, Chia C Wang
Angelica sinensis (AS), one of the most versatile herbal medicines remains widely used due to its multi-faceted pharmacologic activities. Besides its traditional use as the blood-nourishing tonic, its anti-hypertensive, anti-cardiovascular, neuroprotective and anti-cancer effects have been reported. Albeit the significant therapeutic effects, how AS exerts such diverse efficacies from the molecular level remains elusive. Here we investigate the influences of AS and four representative phthalide derivatives from AS on the structure and function of hemoglobin (Hb)...
July 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28710279/ubmes-and-ubfluor-novel-probes-for-rbr-e3-ubiquitin-ligase-parkin
#14
Sungjin Park, Peter K Foote, David T Krist, Sarah E Rice, Alexander V Statsyuk
Ring-Between-Ring (RBR) E3 ligases have been implicated in autoimmune disorders and neurodegenerative diseases. The functions of many RBR E3s are poorly defined and their regulation is complex, involving posttranslational modifications and allosteric regulation with other protein partners. The functional complexity of RBRs, coupled with the complexity of the native ubiquitination reaction that requires ATP, E1, and E2 enzymes, makes it difficult to study these ligases for basic research and therapeutic purposes...
July 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28710278/phosphorylation-of-human-aquaporin-2-aqp2-allosterically-controls-its-interaction-with-the-lysosomal-trafficking-protein-lip5
#15
Jennifer Virginia Roche, Sabeen Survery, Stefan Kreida, Veronika Nesverova, Henry Ampah-Korsah, Maria Gourdon, Peter M T Deen, Susanna Toernroth-Horsefield
The interaction between the renal water channel aquaporin-2 (AQP2) and the lysosomal trafficking regulator-interacting protein LIP5 targets AQP2 to multivesicular bodies and facilitates lysosomal degradation. This interaction is part of a process which controls AQP2 apical membrane abundance in a vasopressin-dependent manner, allowing for urine volume adjustment. Vasopressin regulates phosphorylation at four sites within the AQP2 C-terminus (S256, S261, S264, T269), of which S256 is crucial and sufficient for AQP2 translocation from storage vesicles to the apical membrane...
July 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28709671/mechanism-and-properties-of-positive-allosteric-modulation-of-n-methyl-d-aspartate-receptors-by-6-alkyl-2-naphthoic-acid-derivatives
#16
Kiran Sapkota, Mark W Irvine, Guangyu Fang, Erica S Burnell, Neil Bannister, Arturas Volianskis, Georgia R Culley, Shashank M Dravid, Graham L Collingridge, David E Jane, Daniel T Monaghan
The theory that N-methyl-d-aspartate receptor (NMDAR) hypofunction is responsible for the symptoms of schizophrenia is well supported by many pharmacological and genetic studies. Accordingly, positive allosteric modulators (PAMs) that augment NMDAR signaling may be useful for treating schizophrenia. Previously we have identified several NMDAR PAMs containing a carboxylic acid attached to naphthalene, phenanthrene, or coumarin ring systems. In this study, we describe several functional and mechanistic properties of UBP684, a 2-naphthoic acid derivative, which robustly potentiates agonist responses at each of the four GluN1a/GluN2 receptors and at neuronal NMDARs...
July 11, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28708892/cross-recognition-of-a-pit-viper-crotalinae-polyspecific-antivenom-explored-through-high-density-peptide-microarray-epitope-mapping
#17
Mikael Engmark, Bruno Lomonte, José María Gutiérrez, Andreas H Laustsen, Federico De Masi, Mikael R Andersen, Ole Lund
Snakebite antivenom is a 120 years old invention based on polyclonal mixtures of antibodies purified from the blood of hyper-immunized animals. Knowledge on antibody recognition sites (epitopes) on snake venom proteins is limited, but may be used to provide molecular level explanations for antivenom cross-reactivity. In turn, this may help guide antivenom development by elucidating immunological biases in existing antivenoms. In this study, we have identified and characterized linear elements of B-cell epitopes from 870 pit viper venom protein sequences by employing a high-throughput methodology based on custom designed high-density peptide microarrays...
July 14, 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28708827/deciphering-the-regulation-of-p2x4-receptor-channel-gating-by-ivermectin-using-markov-models
#18
Laurent Mackay, Hana Zemkova, Stanko S Stojilkovic, Arthur Sherman, Anmar Khadra
The P2X4 receptor (P2X4R) is a member of a family of purinergic channels activated by extracellular ATP through three orthosteric binding sites and allosterically regulated by ivermectin (IVM), a broad-spectrum antiparasitic agent. Treatment with IVM increases the efficacy of ATP to activate P2X4R, slows both receptor desensitization during sustained ATP application and receptor deactivation after ATP washout, and makes the receptor pore permeable to NMDG+, a large organic cation. Previously, we developed a Markov model based on the presence of one IVM binding site, which described some effects of IVM on rat P2X4R...
July 14, 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28707143/clinical-sleep-wake-disorders-ii-focus-on-insomnia-and-circadian-rhythm-sleep-disorders
#19
Kai Spiegelhalder, Christoph Nissen, Dieter Riemann
Insomnia and circadian rhythm sleep disorders affect large proportions of the population and have pronounced effects on quality of life and daytime performance. While the neurobiology of insomnia is not yet fully understood, circadian rhythm sleep disorders are assumed to be caused by a mismatch between the individual circadian phase position and the desired sleep-wake schedule. Benzodiazepines and non-benzodiazepine positive allosteric GABAA receptor modulators improve sleep onset and maintenance in the short-term treatment of insomnia...
July 14, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28705990/systemic-pan-ampk-activator-mk-8722-improves-glucose-homeostasis-but-induces-cardiac-hypertrophy
#20
Robert W Myers, Hong-Ping Guan, Juliann Ehrhart, Aleksandr Petrov, Srinivasa Prahalada, Effie Tozzo, Xiaodong Yang, Marc M Kurtz, Maria Trujillo, Dinko Gonzalez Trotter, Danqing Feng, Shiyao Xu, George Eiermann, Marie A Holahan, Daniel Rubins, Stacey Conarello, Xiaoda Niu, Sandra C Souza, Corin Miller, Jinqi Liu, Ku Lu, Wen Feng, Ying Li, Ronald E Painter, James A Milligan, Huaibing He, Franklin Liu, Aimie Ogawa, Douglas Wisniewski, Rory J Rohm, Liyang Wang, Michelle Bunzel, Ying Qian, Wei Zhu, Hongwu Wang, Bindu Bennet, Lisa LaFranco Scheuch, Guillermo E Fernandez, Cai Li, Michael Klimas, Gaochao Zhou, Margaret van Heek, Tesfaye Biftu, Ann Weber, David E Kelley, Nancy Thornberry, Mark D Erion, Daniel M Kemp, Iyassu K Sebhat
5'-Adenosine monophosphate-activated protein kinase (AMPK) is a master regulator of energy homeostasis in eukaryotes. Despite investigations over three decades, the biological roles of AMPK and its potential as a drug target remain incompletely understood, due largely to the lack of optimized pharmacological tools. We now report MK-8722, a potent, direct, allosteric activator of all twelve mammalian AMPK complexes. In rodents and rhesus monkeys, MK-8722-mediated AMPK activation in skeletal muscle induces robust, durable, insulin-independent glucose uptake and glycogen synthesis, with resultant improvements in glycemia and no evidence of hypoglycemia...
July 13, 2017: Science
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