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https://www.readbyqxmd.com/read/29232711/dependence-of-prevalence-of-contiguous-pathways-in-proteins-on-structural-complexity
#1
Kelly M Thayer, Jesse C Galganov, Avram J Stein
Allostery is a regulatory mechanism in proteins where an effector molecule binds distal from an active site to modulate its activity. Allosteric signaling may occur via a continuous path of residues linking the active and allosteric sites, which has been suggested by large conformational changes evident in crystal structures. An alternate possibility is that the signal occurs in the realm of ensemble dynamics via an energy landscape change. While the latter was first proposed on theoretical grounds, increasing evidence suggests that such a control mechanism is plausible...
2017: PloS One
https://www.readbyqxmd.com/read/29231251/mechanoactivation-of-the-angiotensin-ii-type-1-receptor-induces-%C3%AE-arrestin-biased-signaling-through-g%C3%AE-i-coupling
#2
Jialu Wang, Kenji Hanada, Clarice Gareri, Howard A Rockman
Ligand activation of the angiotensin II type 1 receptor (AT1R), a member of the G protein-coupled receptor (GPCR) family, stimulates intracellular signaling to mediate a variety of physiological responses. The AT1R is also known to be a mechanical sensor. When activated by mechanical stretch, the AT1R can signal via the multifunctional adaptor protein β-arrestin, rather than through classical heterotrimeric G protein pathways. To date, the AT1R conformation induced by membrane stretch in the absence of ligand was thought to be the same as that induced by β-arrestin-biased agonists, which selectively engage β-arrestin thereby preventing G protein coupling...
December 12, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29230960/ciq-a-positive-allosteric-modulator-of-glun2c-d-containing-n-methyl-d-aspartate-receptors-rescues-striatal-synaptic-plasticity-deficit-in-a-mouse-model-of-parkinson-s-disease
#3
Mona Nouhi, Xiaoqun Zhang, Ning Yao, Karima Chergui
AIMS: To investigate if CIQ, a positive allosteric modulator of N-methyl-d-aspartate receptors (NMDARs) containing GluN2C/D subunits, rescues the loss of long-term potentiation (LTP) and forelimb-use asymmetry in a mouse model of Parkinson's disease (PD). METHODS: We have used electrophysiology in brain slices and the cylinder test to examine the effect of CIQ on glutamatergic synaptic transmission, synaptic plasticity, and forelimb-use in the unilateral 6-hydroxydopamine-lesion mouse model of PD...
December 11, 2017: CNS Neuroscience & Therapeutics
https://www.readbyqxmd.com/read/29229866/allosteric-histidine-switch-for-regulation-of-intracellular-zinc-ii-fluctuation
#4
Rongfeng Zhu, Yanqun Song, Haiping Liu, Yufei Yang, Shenlin Wang, Chengqi Yi, Peng R Chen
Metalloregulators allosterically control transcriptional activity through metal binding-induced reorganization of ligand residues and/or hydrogen bonding networks, while the coordination atoms on the same ligand residues remain seldom changed. Here we show that the MarR-type zinc transcriptional regulator ZitR switches one of its histidine nitrogen atoms for zinc coordination during the allosteric control of DNA binding. The Zn(II)-coordination nitrogen on histidine 42 within ZitR's high-affinity zinc site (site 1) switches from Nε2 to Nδ1 upon Zn(II) binding to its low-affinity zinc site (site 2), which facilitates ZitR's conversion from the nonoptimal to the optimal DNA-binding conformation...
December 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29229835/o-glcnacylation-destabilizes-the-active-tetrameric-pkm2-to-promote-the-warburg-effect
#5
Yang Wang, Jia Liu, Xin Jin, Dapeng Zhang, Dongxue Li, Fengqi Hao, Yunpeng Feng, Shan Gu, Fanlin Meng, Miaomiao Tian, Yi Zheng, Ling Xin, Xinbo Zhang, Xue Han, L Aravind, Min Wei
The Warburg effect, characterized by increased glucose uptake and lactate production, is a well-known universal across cancer cells and other proliferating cells. PKM2, a splice isoform of the pyruvate kinase (PK) specifically expressed in these cells, serves as a major regulator of this metabolic reprogramming with an adjustable activity subjected to numerous allosteric effectors and posttranslational modifications. Here, we have identified a posttranslational modification on PKM2, O-GlcNAcylation, which specifically targets Thr405 and Ser406, residues of the region encoded by the alternatively spliced exon 10 in cancer cells...
December 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29229763/assaying-kinase-activity-of-the-tpl-2-nf-%C3%AE%C2%BAb1-p105-abin-2-complex-using-an-optimal-peptide-substrate
#6
Sandra Kümper, Thorsten Gantke, Chao-Sheng Chen, Yasmina Soneji, Michael J Pattison, Probir Chakravarty, Svend Kjær, Daniel Thomas, Carl Haslam, Bill J Leavens, David House, David J Powell, Steve C Ley
The MKK1/2 kinase TPL-2 is critical for the production of Tumour Necrosis Factor α (TNF) in innate immune responses and a potential anti-inflammatory drug target. Several earlier pharmaceutical company screens with the isolated TPL-2 kinase domain have identified small molecule inhibitors that specifically block TPL-2 signalling in cells but none of these have progressed to clinical development. We have previously shown that TPL-2 catalytic activity regulates TNF production by macrophages while associated with NF-κB1 p105 and ABIN-2, independently of MKK1/2 phosphorylation via an unknown downstream substrate...
December 11, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/29229699/the-nitrogen-regulatory-pii-protein-glnb-and-n-acetyl-glucosamine-6-phosphate-epimerase-nane-allosterically-activate-glucosamine-6-phosphate-deaminase-nagb-in-escherichia-coli
#7
Irina A Rodionova, Norman Goodacre, Mohan Babu, Andrew Emili, Peter Uetz, Milton H Saier
Amino sugars are good sources of both ammonia and fructose-6-phosphate, produced by glucosamine 6-phosphate deaminase, NagB. NagB is known to be allosterically regulated by N-acetyl-glucosamine 6-phosphate (GlcNAc-6P) and the phosphocarrier protein of the bacterial phosphotransferase system, HPr, in Escherichia coli We provide evidence that NanE, GlcNAc-6P epimerase, and the uridylylated PII protein also allosterically activate NagB by direct protein-protein interactions. NanE is essential for neuraminic acid (NANA) and N-acetylmannosamine (ManNAc) utilization, and PII is known to be a central metabolic nitrogen regulator...
December 11, 2017: Journal of Bacteriology
https://www.readbyqxmd.com/read/29228983/characterization-of-interactions-between-hepatitis-c-virus-ns5b-polymerase-annexin-a2-and-rna-effects-on-ns5b-catalysis-and-allosteric-inhibition
#8
Sara M Ø Solbak, Eldar Abdurakhmanov, Anni Vedeler, U Helena Danielson
BACKGROUND: Direct acting antivirals (DAAs) provide efficient hepatitis C virus (HCV) therapy and clearance for a majority of patients, but are not available or effective for all patients. They risk developing HCV-induced hepatocellular carcinoma (HCC), for which the mechanism remains obscure and therapy is missing. Annexin A2 (AnxA2) has been reported to co-precipitate with the non-structural (NS) HCV proteins NS5B and NS3/NS4A, indicating a role in HCC tumorigenesis and effect on DAA therapy...
December 11, 2017: Virology Journal
https://www.readbyqxmd.com/read/29227934/gabaa-receptor-activity-modulating-piperine-analogs-in-vitro-metabolic-stability-metabolite-identification-cyp450-reaction-phenotyping-and-protein-binding
#9
Volha Zabela, Timm Hettich, Götz Schlotterbeck, Laurin Wimmer, Marko D Mihovilovic, Fabrice Guillet, Belkacem Bouaita, Bénédicte Shevchenko, Matthias Hamburger, Mouhssin Oufir
In a screening of natural products for allosteric modulators of GABAA receptors (γ-aminobutyric acid type A receptor), piperine was identified as a compound targeting a benzodiazepine-independent binding site. Given that piperine is also an activator of TRPV1 (transient receptor potential vanilloid type 1) receptors involved in pain signaling and thermoregulation, a series of piperine analogs were prepared in several cycles of structural optimization, with the aim of separating GABAA and TRPV1 activating properties...
December 2, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/29227625/genetic-reduction-or-negative-modulation-of-mglu7-does-not-impact-anxiety-and-fear-learning-phenotypes-in-a-mouse-model-of-mecp2-duplication-syndrome
#10
Nicole M Fisher, Rocco G Gogliotti, Sheryl Anne D Vermudez, Branden J Stansley, P Jeffrey Conn, Colleen M Niswender
Rett syndrome and MECP2 Duplication syndrome are neurodevelopmental disorders attributed to loss-of-function mutations in, or duplication of, the gene encoding Methyl-CpG-Binding Protein 2 (MeCP2), respectively. We recently reported decreased expression and function of the metabotropic glutamate receptor 7 (mGlu7) in a mouse model of Rett syndrome. Positive allosteric modulation of mGlu7 activity was sufficient to improve several disease phenotypes including cognition. Here, we tested the hypothesis that mGlu7 expression would be reciprocally regulated in a mouse model of MECP2 Duplication syndrome, such that negative modulation of mGlu7 activity would exert therapeutic benefit...
December 11, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29223796/species-specific-rna-a-to-i-editing-of-mosquito-rdl-modulates-gaba-potency-and-influences-agonistic-potentiating-and-antagonistic-actions-of-ivermectin
#11
Jennina Taylor-Wells, Anish Senan, Isabel Bermudez, Andrew K Jones
The insect GABA receptor, RDL, is the target of several classes of pesticides. The peptide sequences of RDL are generally highly conserved between diverse insects. However, RNA A-to-I editing can effectively alter amino acid residues of RDL in a species specific manner, which can affect the potency of GABA and possibly insecticides. We report here that RNA A-to-I editing alters the gene products of Rdl in three mosquito disease vectors, recoding five amino acid residues in RDL of Aedes aegypti and six residues in RDLs of Anopheles gambiae and Culex pipiens, which is the highest extent of editing in RDL observed to date...
December 6, 2017: Insect Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/29223348/distinctive-binding-properties-of-the-negative-allosteric-modulator-3h-sb269-652-at-recombinant-dopamine-d3-receptors
#12
Irene Fasciani, Ilaria Pietrantoni, Mario Rossi, Clotilde Mannoury la Cour, Gabriella Aloisi, Francesco Marampon, Marco Scarselli, Mark J Millan, Roberto Maggio
Recently, employing radioligand displacement and functional coupling studies, we demonstrated that SB269,652 (N-[(1r,4r)-4-[2-(7-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-1H-indole-2-carboxamide) interacts in an atypical manner with dopamine D3 receptor displaying a unique profile reminiscent of a negative allosteric ligand. Here, we characterized the binding of radiolabelled [3H]SB269,652 to human dopamine D3 receptor stably expressed in Chinese Hamster Ovary cells. Under saturating conditions, SB269,652 showed a KD value of ≈ 1nM...
December 6, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29222417/insulin-in-motion-the-a6-a11-disulfide-bond-allosterically-modulates-structural-transitions-required-for-insulin-activity
#13
Bianca van Lierop, Shee Chee Ong, Alessia Belgi, Carlie Delaine, Sofianos Andrikopoulos, Naomi L Haworth, John G Menting, Michael C Lawrence, Andrea J Robinson, Briony E Forbes
The structural transitions required for insulin to activate its receptor and initiate regulation of glucose homeostasis are only partly understood. Here, using ring-closing metathesis, we substitute the A6-A11 disulfide bond of insulin with a rigid, non-reducible dicarba linkage, yielding two distinct stereo-isomers (cis and trans). Remarkably, only the cis isomer displays full insulin potency, rapidly lowering blood glucose in mice (even under insulin-resistant conditions). It also posseses reduced mitogenic activity in vitro...
December 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29221399/long-range-coupling-between-atp-binding-and-lever-arm-regions-in-myosin-via-dielectric-allostery
#14
Takato Sato, Jun Ohnuki, Mitsunori Takano
A protein molecule is a dielectric substance, so the binding of a ligand is expected to induce dielectric response in the protein molecule, considering that ligands are charged or polar in general. We previously reported that binding of adenosine triphosphate (ATP) to molecular motor myosin actually induces such a dielectric response in myosin due to the net negative charge of ATP. By this dielectric response, referred to as "dielectric allostery," spatially separated two regions in myosin, the ATP-binding region and the actin-binding region, are allosterically coupled...
December 7, 2017: Journal of Chemical Physics
https://www.readbyqxmd.com/read/29220747/effects-of-group-ii-metabotropic-glutamate-receptor-modulation-on-ethanol-and-sucrose-seeking-and-consumption-in-the-rat
#15
Kyle A Windisch, Cristine L Czachowski
Previous studies suggest that group II metabotropic glutamate receptors (mGluR2/3) are involved in regulating ethanol-seeking and consumption. The mGluR2/3 agonist LY379268 (LY37) and selective mGluR2 positive allosteric modulator biphenyl‑indanone A (BINA) were used to investigate the relative contribution of mGlu2 and mGlu3 receptors on ethanol- and sucrose-seeking and consumption. A microinjection study was then performed to examine the role of nucleus accumbens (NAc) core mGluR2/3 on ethanol-seeking. For the systemic experiments, separate groups of male Wistar rats [LY37 (0-2...
September 23, 2017: Alcohol
https://www.readbyqxmd.com/read/29220653/a-poly-adp-ribose-trigger-releases-the-auto-inhibition-of-a-chromatin-remodeling-oncogene
#16
Hari R Singh, Aurelio P Nardozza, Ingvar R Möller, Gunnar Knobloch, Hans A V Kistemaker, Markus Hassler, Nadine Harrer, Charlotte Blessing, Sebastian Eustermann, Christiane Kotthoff, Sébastien Huet, Felix Mueller-Planitz, Dmitri V Filippov, Gyula Timinszky, Kasper D Rand, Andreas G Ladurner
DNA damage triggers chromatin remodeling by mechanisms that are poorly understood. The oncogene and chromatin remodeler ALC1/CHD1L massively decompacts chromatin in vivo yet is inactive prior to DNA-damage-mediated PARP1 induction. We show that the interaction of the ALC1 macrodomain with the ATPase module mediates auto-inhibition. PARP1 activation suppresses this inhibitory interaction. Crucially, release from auto-inhibition requires a poly-ADP-ribose (PAR) binding macrodomain. We identify tri-ADP-ribose as a potent PAR-mimic and synthetic allosteric effector that abrogates ATPase-macrodomain interactions, promotes an ungated conformation, and activates the remodeler's ATPase...
December 7, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29217773/a-potent-selective-and-orally-bioavailable-inhibitor-of-the-protein-tyrosine-phosphatase-ptp1b-improves-insulin-and-leptin-signaling-in-animal-models
#17
Navasona Krishnan, Konstantis F Konidaris, Gilles Gasser, Nicholas K Tonks
The protein tyrosine phosphatase PTP1B is a negative regulator of insulin and leptin signaling, and a highly validated therapeutic target for diabetes and obesity. Conventional approaches to drug development have produced potent and specific PTP1B inhibitors, but these inhibitors lack oral bioavailability, which limits their potential for drug development. Here we report that DPM-1001, an analogue of the specific PTP1B inhibitor trodusquemine (MSI-1436), is a potent, specific and orally bioavailable inhibitor of PTP1B...
December 7, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29216799/flavonoids-as-potent-allosteric-inhibitors-of-protein-tyrosine-phosphatase-1b-molecular-dynamics-simulation-and-free-energy-calculation
#18
Farshid Zargari, Maryam Lotfi, Omolbanin Shahraki, Zahra Nikfarjam, Jafar Shahraki
Protein tyrosine phosphatase 1B (PTP1B) is a member of the PTP superfamily which is considered to be a negative regulator of insulin receptor (IR) signalling pathway. PTP1B is a promising drug target for the treatment of type 2 diabetes, obesity and cancer. The existence of allosteric site in PTP1B has turned the researcher's attention to an alternate strategy for inhibition of this enzyme. Herein, the molecular interactions between the allosteric site of PTP1B with three non-competitive flavonoids, (MOR), (MOK), and (DPO) have been investigated...
December 7, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/29215013/allosteric-pyruvate-kinase-based-logic-gate-synergistically-senses-energy-and-sugar-levels-in-mycobacterium-tuberculosis
#19
Wenhe Zhong, Liang Cui, Boon Chong Goh, Qixu Cai, Peiying Ho, Yok Hian Chionh, Meng Yuan, Abbas El Sahili, Linda A Fothergill-Gilmore, Malcolm D Walkinshaw, Julien Lescar, Peter C Dedon
Pyruvate kinase (PYK) is an essential glycolytic enzyme that controls glycolytic flux and is critical for ATP production in all organisms, with tight regulation by multiple metabolites. Yet the allosteric mechanisms governing PYK activity in bacterial pathogens are poorly understood. Here we report biochemical, structural and metabolomic evidence that Mycobacterium tuberculosis (Mtb) PYK uses AMP and glucose-6-phosphate (G6P) as synergistic allosteric activators that function as a molecular "OR logic gate" to tightly regulate energy and glucose metabolism...
December 7, 2017: Nature Communications
https://www.readbyqxmd.com/read/29214652/pharmacology-in-translation-the-preclinical-and-early-clinical-profile-of-the-novel-%C3%AE-2-3-functionally-selective-gabaa-receptor-positive-allosteric-modulator-pf-06372865
#20
Sarah A Nickolls, Rachel Gurrell, Guido van Amerongen, Juha Kammonen, Lishuang Cao, Adam R Brown, Clara Stead, Andy Mead, Christine Watson, Cathleen Hsu, Robert M Owen, Andy Pike, Rebecca L Fish, Laigao Chen, Ruolun Qiu, Evan D Morris, Gang Feng, Mark Whitlock, Donal Gorman, Joop van Gerven, David S Reynolds, Pinky Dua, Richard P Butt
BACKGROUND AND PURPOSE: Benzodiazepines (BZDs), non-selective positive allosteric modulators (PAMs) of GABAA receptors, have significant side-effects that limit their clinical utility. As many of these side-effects are mediated by the α1 subunit there has been a concerted effort to develop α2/3 subtype-selective PAMs. EXPERIMENTAL APPROACH: In vitro screening assays were used to identify molecules with functional selectivity for receptors containing α2/3 subunits over those containing α1 subunits...
December 7, 2017: British Journal of Pharmacology
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