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Yuanbiao Qiao, Li Song, Chenchen Zhu, Qian Wang, Tianyan Guo, Yanhua Yan, Qingshan Li
The data presented here are related to a research article entitled "Development of a phosphorylated Momordica charantia protein system for inhibiting susceptible dose-dependent C. albicans to available antimycotics: An allosteric regulation of protein" (Qiao et al., 2017) [1]. The data set includes three portions: (1) a relationship between reaction velocities of protein phosphorylation as a function of the substrate concentrations, determined in enzymatic reactions in aid of protein kinases; (2) a result of antifungal susceptibility testing of C...
December 2017: Data in Brief
David Grahame Hardie, Sheng-Cai Lin
Orthologues of AMP-activated protein kinase (AMPK) occur in essentially all eukaryotes as heterotrimeric complexes comprising catalytic α subunits and regulatory β and γ subunits. The canonical role of AMPK is as an energy sensor, monitoring levels of the nucleotides AMP, ADP, and ATP that bind competitively to the γ subunit. Once activated, AMPK acts to restore energy homeostasis by switching on alternate ATP-generating catabolic pathways while switching off ATP-consuming anabolic pathways. However, its ancestral role in unicellular eukaryotes may have been in sensing of glucose rather than energy...
2017: F1000Research
Samir Takillah, Jérémie Naudé, Steve Didienne, Claude Sebban, Brigitte Decros, Esther Schenker, Michael Spedding, Alexandre Mourot, Jean Mariani, Philippe Faure
Anxiolytic drugs are widely used in the elderly, a population particularly sensitive to stress. Stress, aging and anxiolytics all affect low-frequency oscillations in the hippocampus and prefrontal cortex (PFC) independently, but the interactions between these factors remain unclear. Here, we compared the effects of stress (elevated platform, EP) and anxiolytics (diazepam, DZP) on extracellular field potentials (EFP) in the PFC, parietal cortex and hippocampus (dorsal and ventral parts) of adult (8 months) and aged (18 months) Wistar rats...
2017: Frontiers in Aging Neuroscience
Pavel Mareš
Arrest of seizures is due to an active inhibition and is followed in mature brain by period of refractoriness markedly present one min after the end of seizures. To study changes in cortical excitability after epileptic seizures we used electrical stimulation of sensorimotor cortical area in immature rats - 25-day-old ones with mature postictal refractoriness and 12-day-old where postictal potentiation of afterdischarges (ADs) is present instead of refractoriness at one minute after the end of the conditioning AD...
October 12, 2017: European Journal of Pharmacology
Reid V Wilkening, Glenn C Capodagli, Atul Khataokar, Kaitlyn M Tylor, Matthew B Neiditch, Michael J Federle
Rap/Rgg/NprR/PlcR/PrgX (RRNPP) quorum-sensing systems use extracellular peptide pheromones that are detected by cytoplasmic receptors to regulate gene expression in firmicute bacteria. Rgg-type receptors are allosterically regulated through direct pheromone binding to control transcriptional activity; however, the receptor activation mechanism remains poorly understood. Previous work has identified a disulfide bond between Cys-45 residues within the homodimer interface of Rgg2 from Streptococcus dysgalactiae (Rgg2Sd)...
October 13, 2017: Journal of Biological Chemistry
Shaoyong Lu, Mingfei Ji, Duan Ni, Jian Zhang
Hidden allosteric sites, as a novel type of allosteric site, are invisible in ligand-unbound (apo) crystal structures, but can emerge in ligand-bound (holo) crystal structures when a specific ligand binds to, and stabilizes, a unique conformation favored by the ligand. However, the identification of these sites is a significant challenge. Several computational and experimental approaches have been developed to identify such sites in proteins. Here, we outline these approaches, with a focus on examples of the successful use of such techniques...
October 10, 2017: Drug Discovery Today
Huafang Ding, Xing Hu, Ximing Xu, Guowen Zhang, Deming Gong
Glycemic control which can be efficaciously regulated by inhibiting α-glucosidase activity is an effective therapy for diabetes mellitus. This work is to investigate the kinetics and inhibition mechanism of oleanolic acid and ursolic acid on α-glucosidase. Oleanolic acid and ursolic acid exhibited potent inhibitory activities with IC50 values of (6.35±0.02)×10(-6) and (1.69±0.03)×10(-5)molL(-1) respectively in a reversible and non-competitive manner. Both of them binding to α-glucosidase induced the conformational change and intrinsic fluorescence quenching of α-glucosidase...
October 10, 2017: International Journal of Biological Macromolecules
Marta Marszalek-Grabska, Ewa Gibula-Bruzda, Anna Bodzon-Kulakowska, Piotr Suder, Kinga Gawel, Sylwia Talarek, Joanna Listos, Ewa Kedzierska, Wojciech Danysz, Jolanta H Kotlinska
Repeated exposure to and withdrawal from ethanol induces deficits in spatial reversal learning. Data indicate that metabotropic glutamate 5 (mGlu5) receptors are implicated in synaptic plasticity and learning and memory. These receptors functionally interact with N-methyl-d-aspartate (NMDA) receptors, and activation of one type results in the activation of the other. We examined whether (S)-(4-fluorophenyl)(3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-piperidin-1-yl (ADX-47273), a positive allosteric modulator (PAM) of mGlu5 receptor, attenuates deficits in reversal learning induced by withdrawal (11-13days) from 'binge-like' ethanol input (5...
October 10, 2017: Behavioural Brain Research
Mingxuan Gao, Jingjing Guo, Yanling Song, Zhi Zhu, Chaoyong James Yang
As a vital enzyme in DNA phosphorylation and restoration, T4 polynuceotide kinase (T4 PNK) has aroused great interest in recent years. Numerous strategies have been established for highly sensitive detection of T4 PNK based on diverse signal amplification techniques. However, they often need sophisticated design, a variety of auxiliary reagents and enzymes, or cumbersome manipulations. Herein, we have designed a new kind of allosteric aptamer probe consisting of streptavidin aptamer (SA aptamer) and the complementary DNA (cDNA) for simple detection of T4 PNK without signal amplification and with minimized interference in complex biological samples...
October 13, 2017: ACS Applied Materials & Interfaces
Emi Kurimoto, Satoru Matsuda, Yuji Shimizu, Yuu Sako, Takao Mandai, Takahiro Sugimoto, Hiroki Sakamoto, Haruhide Kimura
Activation of muscarinic M1 receptor (M1R) is a promising approach for improving cognitive impairment in Alzheimer's disease. However, an M1 selective positive allosteric modulator (PAM), benzyl quinolone carboxylic acid (BQCA), at 30 mg/kg, induced diarrhea in wild-type mice, but not in M1R knock-out mice. Moreover, BQCA (0.1-1000 nM) augmented electric field stimulation (EFS) -induced ileum contraction in an in vitro Magnus assay. Thus, we decided to establish a drug-screening strategy to discover novel M1 PAMs producing potent cognitive improvement with minimized gastrointestinal (GI) dysfunction...
October 12, 2017: Journal of Pharmacology and Experimental Therapeutics
Yu Zhou, Huanghe Yang, Jianmin Cui, Christopher J Lingle
For those interested in the machinery of ion channel gating, the Ca(2+) and voltage-activated BK K(+) channel provides a compelling topic for investigation, by virtue of its dual allosteric regulation by both voltage and intracellular Ca(2+) and because its large-single channel conductance facilitates detailed kinetic analysis. Over the years, biophysical analyses have illuminated details of the allosteric regulation of BK channels and revealed insights into the mechanism of BK gating, e.g., inner cavity size and accessibility and voltage sensor-pore coupling...
October 12, 2017: Journal of General Physiology
K V Niessen, T Seeger, S Rappenglück, T Wein, G Höfner, K T Wanner, H Thiermann, F Worek
The primary toxic mechanism of organophosphorus compounds, i.e. nerve agents or pesticides, is based on the irreversible inhibition of acetylcholinesterase. In consequence of the impaired hydrolysis, the neurotransmitter acetylcholine accumulates in cholinergic synapses and disturbs functional activity of nicotinic and muscarinic acetylcholine receptors by overstimulation and subsequent desensitization. The resulting cholinergic syndrome will become acute life-threatening, if not treated adequately. The current standard treatment, consisting of administration of a competitive mAChR antagonist (e...
October 9, 2017: Toxicology Letters
Christine Burlein, Cheng Wang, Xu Min, Triveni Bhatt, Mark Stahlhut, Yangsi Ou, Gregory C Adam, Jeffrey Heath, Daniel J Klein, John Sanders, Kartik Narayan, Pravien Abeywickrema, Mee Ra Heo, Steven S Carroll, Jay A Grobler, Sujata Sharma, Tracy L Diamond, Antonella Converso, Daniel J Krosky
Allosteric integrase inhibitors (ALLINIs) bind to the lens epithelial-derived growth factor (LEDGF) pocket on HIV-1 integrase (IN) and possess potent antiviral effects. Rather than blocking proviral integration, ALLINIs trigger IN conformational changes that have catastrophic effects on viral maturation, rendering the virions assembled in the presence of ALLINIs non-infectious. A high-throughput screen for compounds that disrupt the IN·LEDGF interaction was executed, and extensive triage led to the identification of a t-butylsulfonamide series, as exemplified by 1...
October 12, 2017: ACS Chemical Biology
Roberta Russo, Daniela Giordano, Gianluca Paredi, Francesco Marchesani, Lisa Milazzo, Giovanna Altomonte, Pietro Del Canale, Stefania Abbruzzetti, Paolo Ascenzi, Guido di Prisco, Cristiano Viappiani, Angela Fago, Stefano Bruno, Giulietta Smulevich, Cinzia Verde
A large amount of data is currently available on the adaptive mechanisms of polar bony fish hemoglobins, but structural information on those of cartilaginous species is scarce. This study presents the first characterisation of the hemoglobin system of one of the longest-living vertebrate species (392 ± 120 years), the Arctic shark Somniosus microcephalus. Three major hemoglobins are found in its red blood cells and are made of two copies of the same α globin combined with two copies of three very similar β subunits...
2017: PloS One
Lingyun Qin, Huili Liu, Rong Chen, Jingjing Zhou, Xiyao Cheng, Yao Chen, Yongqi Huang, Zhengding Su
The oncoprotein MdmX (Mouse double minute X) is highly homologous to Mdm2 (Mouse double minute 2) regarding their amino acid sequences and three-dimensional conformations, but Mdm2 inhibitors exhibit very weak affinity for MdmX, providing an excellent model for exploring how protein conformation distinguishes and adapts inhibitor-binding. The intrinsic conformation flexibility of proteins plays pivotal roles in determining and predicting the binding properties and the design of inhibitors. Although the molecular dynamics simulation approach enables the understanding of protein-ligand interactions, the mechanism un-derlying how a flexible binding pocket adapts an inhibitor is less explored experimentally...
October 12, 2017: Biochemistry
Jing Li, Jordan T White, Harry Saavedra, James O Wrabl, Hesam N Motlagh, Kaixian Liu, James Sowers, Trina Schroer, E Brad Thompson, Vincent J Hilser
Intrinsically disordered proteins (IDPs) present a functional paradox because they lack stable tertiary structure, but nonetheless play a central role in signaling, utilizing a process known as allostery. Historically, allostery in structured proteins has been interpreted in terms of propagated structural changes that are induced by effector binding. Thus, it is not clear how IDPs, lacking such well-defined structures, can allosterically affect function. Here we show a mechanism by which an IDP can allosterically control function by simultaneously tuning transcriptional activation and repression, using a novel strategy that relies on the principle of 'energetic frustration'...
October 12, 2017: ELife
Vikas Chandra, Dalei Wu, Sheng Li, Nalini Potluri, Youngchang Kim, Fraydoon Rastinejad
Assessing the physical connections and allosteric communications in multi-domain nuclear receptor (NR) polypeptides has remained challenging, with few crystal structures available to show their overall structural organizations. Here we report the quaternary architecture of multi-domain retinoic acid receptor β-retinoic X receptor α (RARβ-RXRα) heterodimer bound to DNA, ligands and coactivator peptides, examined through crystallographic, hydrogen-deuterium exchange mass spectrometry, mutagenesis and functional studies...
October 11, 2017: Nature Communications
Razak Hussain, Indu Kumari, Shikha Sharma, Mushtaq Ahmed, Tabreiz Ahmad Khan, Yusuf Akhter
Trichothecenes are the secondary metabolites produced by Trichoderma spp. Some of these molecules have been reported for their ability to stimulate plant growth by suppressing plant diseases and hence enabling Trichoderma spp. to be efficiently used as biocontrol agents in modern agriculture. Many of the proteins involved in the trichothecenes biosynthetic pathway in Trichoderma spp. are encoded by the genes present in the tri cluster. Tri4 protein catalyzes three consecutive oxygenation reaction steps during biosynthesis of isotrichodiol in the trichothecenes biosynthetic pathway, while tri11 protein catalyzes the C4 hydroxylation of 12, 13-epoxytrichothec-9-ene to produce trichodermol...
October 10, 2017: Journal of Biological Inorganic Chemistry: JBIC
Young Jun An, Sara E Rowland, Jung-Hyun Na, Dario Spigolon, Seung Kon Hong, Yeo Joon Yoon, Jung-Hyun Lee, Frank T Robb, Sun-Shin Cha
The chaperonins (CPNs) are megadalton sized hollow complexes with two cavities that open and close to encapsulate non-native proteins. CPNs are assigned to two sequence-related groups that have distinct allosteric mechanisms. In Group I CPNs a detachable co-chaperone, GroES, closes the chambers whereas in Group II a built-in lid closes the chambers. Group I CPNs have a bacterial ancestry, whereas Group II CPNs are archaeal in origin. Here we describe open and closed crystal structures representing a new phylogenetic branch of CPNs...
October 10, 2017: Nature Communications
Andreja Šarlah, Andrej Vilfan
Motor proteins generally have a two-way coupling between the ATP hydrolysis site, the lever movement and the binding affinity for their track, which allows them to perform efficient stepping. Here we explore the minimal requirements for directed motility based on simpler schemes in which the binding/unbinding from the track is decoupled from the ATPase cycle. We show that a directed power stroke alone is not sufficient for motility, but combined with an asymmetry in force-induced unbinding rates it can generate stepping...
2017: PloS One
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