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https://www.readbyqxmd.com/read/29928800/rationalizing-context-dependent-performance-of-dynamic-rna-regulatory-devices
#1
Ross Kent, Samantha Halliwell, Kate Young, Neil Swainston, Neil Dixon
The ability of RNA to sense, regulate and store information is an attractive attribute for a variety of functional applications including the development of regulatory control devices for synthetic biology. RNA folding and function is known to be highly context sensitive, which limits the modularity and reuse of RNA regulatory devices to control different heterologous sequences and genes. We explored the cause and effect of sequence context sensitivity for translational ON riboswitches located in the 5' UTR, by constructing and screening a library of N-terminal synonymous codon variants...
June 21, 2018: ACS Synthetic Biology
https://www.readbyqxmd.com/read/29927572/modulation-of-the-allosteric-communication-between-the-polo-box-domain-and-the-catalytic-domain-in-plk1-by-small-compounds
#2
Monika Raab, Mourad Sanhaji, Larissa Pietsch, Isabelle Béquignon, Amanda K Herbrand, Evelyn Süß, Santosh L Gande, Birgit Caspar, Denis Kudlinzki, Krishna Saxena, Sridhar Sreeramulu, Harald Schwalbe, Klaus Strebhardt, Ricardo M Biondi
The Polo-like kinases (Plks) are an evolutionary conserved family of Ser/Thr protein kinases that possess, in addition to the classical kinase domain at the N-terminus, a C-terminal polo-box domain (PBD) that binds to phosphorylated proteins, modulates the kinase activity and its localization. Plk1, which regulates the formation of the mitotic spindle, has emerged as a validated drug target for the treatment of cancer, because it is required for numerous types of cancer cells but not for the cell division in non-cancer cells...
June 21, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29926068/-involvement-of-interaction-between-trpc1-and-orai1-in-calcium-sensing-receptor-mediated-calcium-influx-and-nitric-oxide-generation-in-human-umbilical-vein-endothelial-cells
#3
La-Mei Wang, Na Tang, Hua Zhong, Li-Juan Pang, Chun-Jun Zhang, Fang He
The present study was to investigate the role of the interaction between canonical transient receptor potential channel 1 (TRPC1) and calcium release-activated calcium modulator 1 (Orai1) in extracellular Ca2+ -sensing receptor (CaR)-induced extracellular Ca2+ influx and nitric oxide (NO) production. Human umbilical vein endothelial cells (HUVECs) were incubated with CaR agonist Spermine [activating store-operated calcium channels (SOC) and receptor-operated calcium channels (ROC)] alone or in combination with the following reagents: CaR negative allosteric modulator Calhex231 plus ROC analogue TPA (activating ROC and blocking SOC), Ro31-8220 (PKC inhibitor that activates SOC and blocks ROC) or Go6967 (PKCs and PKCµ inhibitor that activates SOC and blocks ROC)...
June 25, 2018: Sheng Li Xue Bao: [Acta Physiologica Sinica]
https://www.readbyqxmd.com/read/29925258/the-molecular-basis-of-g-protein-coupled-receptor-activation
#4
William I Weis, Brian K Kobilka
G protein-coupled receptors (GPCRs) mediate the majority of cellular responses to external stimuli. Upon activation by a ligand, the receptor binds to a partner heterotrimeric G protein and promotes exchange of GTP for GDP, leading to dissociation of the G protein into α and βγ subunits that mediate downstream signals. GPCRs can also activate distinct signaling pathways through arrestins. Active states of GPCRs form by small rearrangements of the ligand-binding, or orthosteric, site that are amplified into larger conformational changes...
June 20, 2018: Annual Review of Biochemistry
https://www.readbyqxmd.com/read/29925021/gating-currents-in-the-hv1-proton-channel
#5
Victor De La Rosa, Ian Scott Ramsey
The Hv1 proton channel shares striking structural homology with fourth transmembrane helical segment-type voltage-sensor (VS) domains but manifests distinctive functional properties, including a proton-selective "aqueous" conductance and allosteric control of voltage-dependent gating by changes in the transmembrane pH gradient. The mechanisms responsible for Hv1's functional properties remain poorly understood, in part because methods for measuring gating currents that directly report VS activation have not yet been described...
June 19, 2018: Biophysical Journal
https://www.readbyqxmd.com/read/29925016/principles-for-optimal-cooperativity-in-allosteric-materials
#6
Le Yan, Riccardo Ravasio, Carolina Brito, Matthieu Wyart
Allosteric proteins transmit a mechanical signal induced by binding a ligand. However, understanding the nature of the information transmitted and the architectures optimizing such transmission remains a challenge. Here we show, using an in silico evolution scheme and theoretical arguments, that architectures optimized to be cooperative, which efficiently propagate energy, qualitatively differ from previously investigated materials optimized to propagate strain. Although we observe a large diversity of functioning cooperative architectures (including shear, hinge, and twist designs), they all obey the same principle of displaying a mechanism, i...
June 19, 2018: Biophysical Journal
https://www.readbyqxmd.com/read/29924847/protein-dynamic-communities-from-elastic-network-models-align-closely-to-the-communities-defined-by-molecular-dynamics
#7
Sambit Kumar Mishra, Robert L Jernigan
Dynamic communities in proteins comprise the cohesive structural units that individually exhibit rigid body motions. These can correspond to structural domains, but are usually smaller parts that move with respect to one another in a protein's internal motions, key to its functional dynamics. Previous studies emphasized their importance to understand the nature of ligand-induced allosteric regulation. These studies reported that mutations to key community residues can hinder transmission of allosteric signals among the communities...
2018: PloS One
https://www.readbyqxmd.com/read/29924597/screening-a-protein-array-with-synthetic-biotinylated-inorganic-polyphosphate-to-define-the-human-polyp-ome
#8
Cristina Azevedo, Jyoti Singh, Nicole Steck, Alexandre Hofer, Felix A Ruiz, Tanya Singh, Henning J Jessen, Adolfo Saiardi
Phenotypes are established by thigh regulation on protein functions. This regulation can be mediated allosterically, through protein binding, and covalently, through post-translational modification (PTM). The integration of an ever-increasing number of PTMs into regulatory networks enable and define the proteome complexity. Protein PTMs can occur enzymatically and non-enzymatically. Polyphosphorylation, a recently discovered PTM that belongs to the latter category, is the covalent attachment of the linear ortho-phosphate polymer called inorganic polyphosphate (polyP) to lysine residues...
June 20, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29923648/assessment-of-the-interaction-between-the-flux-signaling-metabolite-fructose-1-6-bisphosphate-and-the-bacterial-transcription-factors-cggr-and-cra
#9
Brenda Bley Folly, Alvaro D Ortega, Georg Hubmann, Silke Bonsing-Vedelaar, Hein J Wijma, Pieter van der Meulen, Andreas Milias-Argeitis, Matthias Heinemann
Bacteria regulate cell physiology in response to extra- and intracellular cues. Recent work showed that metabolic fluxes are reported by specific metabolites, whose concentrations correlate with flux through the respective metabolic pathway. An example of a flux-signaling metabolite is fructose-1,6-bisphosphate (FBP). In turn, FBP was proposed to allosterically regulate master regulators of carbon metabolism, Cra in Escherichia coli and CggR in Bacillus subtilis. However, a number of questions on the FBP-mediated regulation of these transcription factors is still open...
June 20, 2018: Molecular Microbiology
https://www.readbyqxmd.com/read/29923088/sialuria-ninth-patient-described-has-a-novel-mutation-in-gne
#10
Noelia Nunez Martinez, Michelle Lipke, Jacqueline Robinson, Bridget Wilcken
Sialuria is a rare autosomal dominant inborn error of metabolism characterized by cytoplasmic accumulation and urinary excretion of gram quantities of free sialic acid due to failure of feedback inhibition of the rate-limiting enzyme in the sialic acid synthesis pathway, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE/MNK). To date, eight cases had been published worldwide, all with heterozygous missense variants at the allosteric site, specifically at Arginine 294 (formerly 263) and Arginine 297 (formerly 266) of GNE...
June 20, 2018: JIMD Reports
https://www.readbyqxmd.com/read/29921957/hepatokin1-is-a-biochemistry-based-model-of-liver-metabolism-for-applications-in-medicine-and-pharmacology
#11
Nikolaus Berndt, Sascha Bulik, Iwona Wallach, Tilo Wünsch, Matthias König, Martin Stockmann, David Meierhofer, Hermann-Georg Holzhütter
The epidemic increase of non-alcoholic fatty liver diseases (NAFLD) requires a deeper understanding of the regulatory circuits controlling the response of liver metabolism to nutritional challenges, medical drugs, and genetic enzyme variants. As in vivo studies of human liver metabolism are encumbered with serious ethical and technical issues, we developed a comprehensive biochemistry-based kinetic model of the central liver metabolism including the regulation of enzyme activities by their reactants, allosteric effectors, and hormone-dependent phosphorylation...
June 19, 2018: Nature Communications
https://www.readbyqxmd.com/read/29915179/post-translational-modifications-in-dna-topoisomerase-2%C3%AE-highlight-the-role-of-a-eukaryote-specific-residue-in-the-atpase-domain
#12
Claire Bedez, Christophe Lotz, Claire Batisse, Arnaud Vanden Broeck, Roland H Stote, Eduardo Howard, Karine Pradeau-Aubreton, Marc Ruff, Valérie Lamour
Type 2 DNA topoisomerases (Top2) are critical components of key protein complexes involved in DNA replication, chromosome condensation and segregation, as well as gene transcription. The Top2 were found to be the main targets of anticancer agents, leading to intensive efforts to understand their functional and physiological role as well as their molecular structure. Post-translational modifications have been reported to influence Top2 enzyme activities in particular those of the mammalian Top2α isoform. In this study, we identified phosphorylation, and for the first time, acetylation sites in the human Top2α isoform produced in eukaryotic expression systems...
June 18, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29913190/neurochemical-changes-underlying-schizophrenia-related-behavior-in-a-modified-forced-swim-test-in-mice
#13
Monika Wożniak, Paulina Cieślik, Marcin Marciniak, Tomasz Lenda, Andrzej Pilc, Joanna M Wieronska
The modified forced swim test (MFST) has excellent predictive validity for investigating the antipsychotic activity of drugs, with particular emphasis on their activity toward negative symptoms of schizophrenia. However, its face and construct validity are less understood. Therefore, in the present study, some biochemical changes within GABAergic and serotonergic neurotransmission that could be related to observed MK-801-induced disturbances and the activity of compounds active at those neurotransmitters were investigated...
June 15, 2018: Pharmacology, Biochemistry, and Behavior
https://www.readbyqxmd.com/read/29912965/screening-and-identification-of-potential-ptp1b-allosteric-inhibitors-using-in-silico-and-in-vitro-approaches
#14
Ranajit Nivrutti Shinde, G Siva Kumar, Shahbaz Eqbal, M Elizabeth Sobhia
Protein tyrosine phosphatase 1B (PTP1B) is a validated therapeutic target for Type 2 diabetes due to its specific role as a negative regulator of insulin signaling pathways. Discovery of active site directed PTP1B inhibitors is very challenging due to highly conserved nature of the active site and multiple charge requirements of the ligands, which makes them non-selective and non-permeable. Identification of the PTP1B allosteric site has opened up new avenues for discovering potent and selective ligands for therapeutic intervention...
2018: PloS One
https://www.readbyqxmd.com/read/29912865/evolution-of-chemokine-receptors-is-driven-by-mutations-in-the-sodium-binding-site
#15
Bruck Taddese, Madeline Deniaud, Antoine Garnier, Asma Tiss, Hajer Guissouma, Hervé Abdi, Daniel Henrion, Marie Chabbert
Chemokines and their receptors (members of the GPCR super-family) are involved in a wide variety of physiological processes and diseases; thus, understanding the specificity of the chemokine receptor family could help develop new receptor specific drugs. Here, we explore the evolutionary mechanisms that led to the emergence of the chemokine receptors. Based on GPCR hierarchical classification, we analyzed nested GPCR sets with an eigen decomposition approach of the sequence covariation matrix and determined three key residues whose mutation was crucial for the emergence of the chemokine receptors and their subsequent divergence into homeostatic and inflammatory receptors...
June 18, 2018: PLoS Computational Biology
https://www.readbyqxmd.com/read/29912863/reversing-allosteric-communication-from-detecting-allosteric-sites-to-inducing-and-tuning-targeted-allosteric-response
#16
Wei-Ven Tee, Enrico Guarnera, Igor N Berezovsky
The omnipresence of allosteric regulation together with the fundamental role of structural dynamics in this phenomenon have initiated a great interest to the detection of regulatory exosites and design of corresponding effectors. However, despite a general consensus on the key role of dynamics most of the earlier efforts on the prediction of allosteric sites are heavily crippled by the static nature of the underlying methods, which are either structure-based approaches seeking for deep surface pockets typical for "traditional" orthosteric drugs or sequence-based techniques exploiting the conservation of protein sequences...
June 18, 2018: PLoS Computational Biology
https://www.readbyqxmd.com/read/29908149/a-hexokinase-2-modulator-for-field-directed-treatment-of-experimental-actinic-keratoses
#17
Vered Behar, Hadas Pahima, Adi Kozminsky-Atias, Nir Arbel, Emmanuel Loeb, Max Herzberg, Oren M Becker
Overexpression of hexokinase 2 (HK2), and its binding to VDAC1 on the outer mitochondrial membrane of cancer cells, is key to their metabolic reprogramming to aerobic glycolysis, which enables them to proliferate. We describe Comp-1, an allosteric small molecule that selectively detaches HK2 from the mitochondria. Detachment of HK2 reduces glycolysis and triggers apoptosis in cancer cells, without affecting HK1 expressing normal cells. The anti-cancer activity of Comp-1 was demonstrated in the UVB-damaged skin model in SKH-1 mice...
June 13, 2018: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/29906470/the-effect-of-intracerebroventricular-allopregnanolone-on-depressive-like-behaviors-of-rats-selectively-bred-for-high-and-low-immobility-in-the-forced-swim-test
#18
Felipe Borges Almeida, Alan Rios Fonseca, Núbia Heidrich, Maurício Schüler Nin, Helena Maria Tannhauser Barros
Depression is a highly incapacitating disorder known to have a multifactorial etiology, including a hereditary genetic background. The neurosteroid allopregnanolone (ALLO) is a positive allosteric modulator of the GABAA receptor and has been shown to have an antidepressant-like effect in animals. This study aimed to assess the behavioral effect of ALLO in animals with different backgrounds of depressive-like activity. An initial population (F0) of male and female Wistar rats was screened for immobility behavior utilizing the Forced Swim Test (FST)...
June 12, 2018: Physiology & Behavior
https://www.readbyqxmd.com/read/29906466/tarps-differentially-affect-the-pharmacology-of-ampakines
#19
Daniel P Radin, Yong-Xin Li, Gary Rogers, Richard Purcell, Arnold Lippa
Transmembrane AMPA receptor regulatory proteins (TARPs) govern AMPA receptor cell surface expression and distinct physiological properties including agonist affinity, desensitization and deactivation kinetics. The prototypical TARP, STG or γ2 and TARPs γ3, γ4, γ7 and γ8 are all expressed to varying degrees in the mammalian brain and differentially regulate AMPAR gating parameters. Positive allosteric AMPA receptor modulators or ampakines alter receptor rates of agonist binding/unbinding, channel opening and can offset receptor desensitization and deactivation...
June 12, 2018: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29906089/programming-chemical-reaction-networks-using-intramolecular-conformational-motions-of-dna
#20
Wei Lai, Lei Ren, Qian Tang, Xiangmeng Qu, Jiang Li, Lihua Wang, Li Li, Chunhai Fan, Hao Pei
Programmable regulation of chemical reaction networks (CRNs) represents a major challenge toward the development of complex molecular devices performing sophisticated motions and functions. Nevertheless, regulation of artificial CRNs is generally energy- and time-intensive as compared to natural regulation. Inspired by allosteric regulation in biological CRNs, we herein develop an intramolecular conformational motion strategy (InCMS) for programmable regulation of DNA CRNs. We design a DNA switch as the regulatory element to program the distance between toehold and branch migration domain...
June 15, 2018: ACS Nano
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