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https://www.readbyqxmd.com/read/28821630/il-17a-deficiency-mitigates-bleomycin-induced-complement-activation-during-lung-fibrosis
#1
Ellyse Cipolla, Amanda J Fisher, Hongmei Gu, Elizabeth A Mickler, Manisha Agarwal, Carol A Wilke, Kevin K Kim, Bethany B Moore, Ragini Vittal
Interleukin 17A (IL-17A) and complement (C') activation have each been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). We have reported that IL-17A induces epithelial injury via TGF-β in murine bronchiolitis obliterans; that TGF-β and the C' cascade present signaling interactions in mediating epithelial injury; and that the blockade of C' receptors mitigates lung fibrosis. In the present study, we investigated the role of IL-17A in regulating C' in lung fibrosis. Microarray analyses of mRNA isolated from primary normal human small airway epithelial cells indicated that IL-17A (100 ng/ml; 24 h; n = 5 donor lungs) induces C' components (C' factor B, C3, and GPCR kinase isoform 5), cytokines (IL8, -6, and -1B), and cytokine ligands (CXCL1, -2, -3, -5, -6, and -16)...
August 17, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28820879/a-kinetic-view-of-gpcr-allostery-and-biased-agonism
#2
J Robert Lane, Lauren T May, Robert G Parton, Patrick M Sexton, Arthur Christopoulos
G-protein-coupled receptors (GPCRs) are one of the most tractable classes of drug targets. These dynamic proteins can adopt multiple active states that are linked to distinct functional outcomes. Such states can be differentially stabilized by ligands interacting with the endogenous agonist-binding orthosteric site and/or by ligands acting via spatially distinct allosteric sites, leading to the phenomena of 'biased agonism' or 'biased modulation'. These paradigms are having a major impact on modern drug discovery, but it is becoming increasingly apparent that 'kinetic context', at the level of both ligand-receptor and receptor-signal pathway kinetics, can have a profound impact on the observation and quantification of these phenomena...
August 18, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28818718/template-selection-and-refinement-considerations-for-modelling-aminergic-gpcr-ligand-complexes
#3
Kaniz F Urmi, Angela M Finch, Renate Griffith
G protein-coupled receptors (GPCRs) are important targets for development of drugs for the treatment of many diseases. However, crystal structures are available for only a small fraction of these membrane bound proteins. Accurate homology models will provide opportunities for effective drug design targeting GPCRs. Recently, several serotonin receptor crystal structures were solved and needed to be evaluated as potential templates. In the first part of this work different measures of similarity in template selection were explored and methods for homology modelling, docking and refinement of aminergic GPCR-ligand complexes were developed and evaluated by comparing models of the D3-R/eticlopride complex with the crystal structure...
July 31, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28813418/mechanism-of-intracellular-allosteric-%C3%AE-2ar-antagonist-revealed-by-x-ray-crystal-structure
#4
Xiangyu Liu, Seungkirl Ahn, Alem W Kahsai, Kai-Cheng Meng, Naomi R Latorraca, Biswaranjan Pani, A J Venkatakrishnan, Ali Masoudi, William I Weis, Ron O Dror, Xin Chen, Robert J Lefkowitz, Brian K Kobilka
G-protein-coupled receptors (GPCRs) pose challenges for drug discovery efforts because of the high degree of structural homology in the orthosteric pocket, particularly for GPCRs within a single subfamily, such as the nine adrenergic receptors. Allosteric ligands may bind to less-conserved regions of these receptors and therefore are more likely to be selective. Unlike orthosteric ligands, which tonically activate or inhibit signalling, allosteric ligands modulate physiologic responses to hormones and neurotransmitters, and may therefore have fewer adverse effects...
August 16, 2017: Nature
https://www.readbyqxmd.com/read/28813000/an-ameliorated-prediction-of-drug-target-interactions-based-on-multi-scale-discrete-wavelet-transform-and-network-features
#5
Cong Shen, Yijie Ding, Jijun Tang, Xinying Xu, Fei Guo
The prediction of drug-target interactions (DTIs) via computational technology plays a crucial role in reducing the experimental cost. A variety of state-of-the-art methods have been proposed to improve the accuracy of DTI predictions. In this paper, we propose a kind of drug-target interactions predictor adopting multi-scale discrete wavelet transform and network features (named as DAWN) in order to solve the DTIs prediction problem. We encode the drug molecule by a substructure fingerprint with a dictionary of substructure patterns...
August 16, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28811548/ligand-binding-modes-from-low-resolution-gpcr-models-and-mutagenesis-chicken-bitter-taste-receptor-as-a-test-case
#6
Antonella Di Pizio, Louisa-Marie Kruetzfeldt, Shira Cheled-Shoval, Wolfgang Meyerhof, Maik Behrens, Masha Y Niv
Bitter taste is one of the basic taste modalities, warning against consuming potential poisons. Bitter compounds activate members of the bitter taste receptor (Tas2r) subfamily of G protein-coupled receptors (GPCRs). The number of functional Tas2rs is species-dependent. Chickens represent an intriguing minimalistic model, because they detect the bitter taste of structurally different molecules with merely three bitter taste receptor subtypes. We investigated the binding modes of several known agonists of a representative chicken bitter taste receptor, ggTas2r1...
August 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28808053/navigating-the-conformational-landscape-of-g-protein-coupled-receptor-kinases-during-allosteric-activation
#7
Xin-Qiu Yao, M Claire Cato, Emily Labudde, Tyler S Beyett, John J G Tesmer, Barry J Grant
G protein-coupled receptors (GPCRs) are essential for transferring extracellular signals into carefully choreographed intracellular responses controlling diverse aspects of cell physiology. The duration of GPCR mediated signaling is primarily regulated via GPCR kinase (GRK)-mediated phosphorylation of activated receptors. Although many GRK structures have been reported, the mechanisms underlying GRK activation are not well understood, in part because it is unknown how these structures map to the conformational landscape available to this enzyme family...
August 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28806271/luminal-chemosensing-in-the-gastroduodenal-mucosa
#8
Izumi Kaji, Jonathan D Kaunitz
PURPOSE OF REVIEW: We report recently published knowledge regarding gut chemosensory mechanisms focusing on nutrient-sensing G protein-coupled receptors (GPCRs) expressed on gut enteroendocrine cells (EECs), tuft cells, and in afferent nerves in the gastroduodenal mucosa and submucosa. RECENT FINDINGS: Gene profiling of EECs and tuft cells have revealed expression of a variety of nutrient-sensing GPCRs. The density of EEC and tuft cells is altered by luminal environmental changes that may occur following bypass surgery or in the presence of mucosal inflammation...
August 12, 2017: Current Opinion in Gastroenterology
https://www.readbyqxmd.com/read/28805948/pathogenic-role-of-adgrg2-in-cbavd-patients-replicated-in-chinese-population
#9
B Yang, J Wang, W Zhang, H Pan, T Li, B Liu, H Li, B Wang
Congenital bilateral absence of the vas deferens (CBAVD) is an important cause of obstructive azoospermia and male infertility worldwide. Cystic fibrosis transmembrane conductance regulator (CFTR) mutations are the main pathogenic cause, although a proportion of cases are still unexplained. Recently, adhesion G protein-coupled receptor G2 (ADGRG2) gene, a novel pathogenic gene for CBAVD was identified. We did a single population replication study in Chinese CBAVD patients to replicate its role in CBAVD developing...
August 14, 2017: Andrology
https://www.readbyqxmd.com/read/28805144/a-qm-protein-ligand-investigation-of-anti-psychotic-drugs-with-the-dopamine-d2-receptor-d2r
#10
Ramin Ekhteiari Salmas, Yusuf Serhat Is, Serdar Durdagi, Matthias Stein, Mine Yurtsever
The dopamine D2 Receptor (D2R) is a member of the G-Protein Coupled Receptor (GPCR) family and plays a critical role in neurotransmission activities in the human brain. Dysfunction in dopamine receptor signaling may lead to mental health illnesses such as schizophrenia and Parkinson's disease. D2R is the target protein of the commonly used anti-psychotic drugs such as risperidone, clozapine, aripiprazole, olanzapine, ziprasidone and quetiapine. Due to their significant side effects and nonselective profiles, the discovery of novel drugs has become a challenge for researchers working in this field...
August 14, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28803732/reck-and-gpr124-are-essential-receptor-cofactors-for-wnt7a-wnt7b-specific-signaling-in-mammalian-cns-angiogenesis-and-blood-brain-barrier-regulation
#11
Chris Cho, Philip M Smallwood, Jeremy Nathans
Reck, a GPI-anchored membrane protein, and Gpr124, an orphan GPCR, have been implicated in Wnt7a/Wnt7b signaling in the CNS vasculature. We show here that vascular endothelial cell (EC)-specific reduction in Reck impairs CNS angiogenesis and that EC-specific postnatal loss of Reck, combined with loss of Norrin, impairs blood-brain barrier (BBB) maintenance. The most N-terminal domain of Reck binds to the leucine-rich repeat (LRR) and immunoglobulin (Ig) domains of Gpr124, and weakening this interaction by targeted mutagenesis reduces Reck/Gpr124 stimulation of Wnt7a signaling in cell culture and impairs CNS angiogenesis...
August 7, 2017: Neuron
https://www.readbyqxmd.com/read/28800957/insight-into-the-mode-of-action-and-selectivity-of-pbrm-a-covalent-steroidal-inhibitor-of-17%C3%AE-hydroxysteroid-dehydrogenase-type-1
#12
Alexandre Trottier, René Maltais, Diana Ayan, Xavier Barbeau, Jenny Roy, Martin Perreault, Richard Poulin, Patrick Lagüe, Donald Poirier
17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) is involved in the biosynthesis of estradiol, the major bioactive endogenous estrogen in mammals, and constitutes an interesting therapeutic target for estrogen-dependent diseases. A steroidal derivative, 3-{[(16β,17β)-3-(2-bromoethyl)-17-hydroxyestra-1,3,5(10)-trien-16-yl]methyl} benzamide (PBRM), has recently been described as a non-estrogenic, irreversible inhibitor of 17β-HSD1. However, the mode of action of this inhibitor and its selectivity profile have not yet been elucidated...
August 8, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28798477/er-k-linked-gpcr-g-protein-fusions-systematically-modulate-second-messenger-response-in-cells
#13
Rabia U Malik, Matthew Dysthe, Michael Ritt, Roger K Sunahara, Sivaraj Sivaramakrishnan
FRET and BRET approaches are well established for detecting ligand induced GPCR-G protein interactions in cells. Currently, FRET/BRET assays rely on co-expression of GPCR and G protein, and hence depend on the stoichiometry and expression levels of the donor and acceptor probes. On the other hand, GPCR-G protein fusions have been used extensively to understand the selectivity of GPCR signaling pathways. However, the signaling properties of fusion proteins are not consistent across GPCRs. In this study, we describe and characterize novel sensors based on the Systematic Protein Affinity Strength Modulation (SPASM) technique...
August 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28798468/the-bitter-taste-receptor-tas2r16-achieves-high-specificity-and-accommodates-diverse-glycoside-ligands-by-using-a-two-faced-binding-pocket
#14
Anu Thomas, Chidananda Sulli, Edgar Davidson, Eli Berdougo, Morganne Phillips, Bridget A Puffer, Cheryl Paes, Benjamin J Doranz, Joseph B Rucker
Although bitter taste receptors (TAS2Rs) are important for human health, little is known of the determinants of ligand specificity. TAS2Rs such as TAS2R16 help define gustatory perception and dietary preferences that ultimately influence human health and disease. Each TAS2R must accommodate a broad diversity of chemical structures while simultaneously achieving high specificity so that diverse bitter toxins can be detected without all foods tasting bitter. However, how these G protein-coupled receptors achieve this balance is poorly understood...
August 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28794944/potent-prearranged-positive-allosteric-modulators-of-the-glucagon-like-peptide-1-receptor
#15
Ben J Jones, Rosario Scopelliti, Alejandra Tomas, Stephen R Bloom, David J Hodson, Johannes Broichhagen
Drugs that allosterically modulate G protein-coupled receptor (GPCR) activity display higher specificity and may improve disease treatment. However, the rational design of compounds that target the allosteric site is difficult, as conformations required for receptor activation are poorly understood. Guided by photopharmacology, a set of prearranged positive allosteric modulators (PAMs) with restricted degrees of freedom was designed and tested against the glucagon-like peptide-1 receptor (GLP-1R), a GPCR involved in glucose homeostasis...
August 2017: ChemistryOpen
https://www.readbyqxmd.com/read/28791865/a-microfluidic-chemical-function-generator-for-probing-dynamic-cell-signaling
#16
Peng Chen, Yiran Guo, Xiaojun Feng, Shuangqian Yan, Jie Wang, Yiwei Li, Wei Du, Bi-Feng Liu
Cellular environments are inherently dynamic and generally involve complex, temporally varying signals. Reconstruction of these environments with high spatial and temporal fidelity and simultaneous imaging of intracellular dynamics in live cells remains a major challenge. In this paper, a microfluidic chemical function generator (μCFG) was proposed for probing cell dynamic signaling with high temporal resolution. By combining a hydrodynamic gating module with a chaotic advection mixing module, the μCFG was able to generate a variety of chemical waveforms, such as digital pulsatile chemical waveforms with a frequency higher than 10 Hz and analog chemical waveforms with a frequency higher than 0...
August 9, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28790412/determination-of-the-endothelin-1-recognition-sites-of-endothelin-receptor-type-a-by-the-directed-degeneration-method
#17
Seong-Gu Han, Sanghwan Ko, Won-Kyu Lee, Sang Taek Jung, Yeon Gyu Yu
G-protein coupled receptors (GPCRs) play indispensable physiological roles in cell proliferation, differentiation, and migration; therefore, identifying the mechanisms by which ligands bind to GPCRs is crucial for developing GPCR-targeting pharmaceutics and for understanding critical biological functions. Although some structural information is available regarding the interactions between GPCRs and their small molecule ligands, knowledge of how GPCRs interact with their corresponding macromolecule ligands, such as peptides and proteins, remains elusive...
August 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28790300/agonist-induced-dimer-dissociation-as-a-macromolecular-step-in-g-protein-coupled-receptor-signaling
#18
Julian Petersen, Shane C Wright, David Rodríguez, Pierre Matricon, Noa Lahav, Aviv Vromen, Assaf Friedler, Johan Strömqvist, Stefan Wennmalm, Jens Carlsson, Gunnar Schulte
G protein-coupled receptors (GPCRs) constitute the largest family of cell surface receptors. They can exist and act as dimers, but the requirement of dimers for agonist-induced signal initiation and structural dynamics remains largely unknown. Frizzled 6 (FZD6) is a member of Class F GPCRs, which bind WNT proteins to initiate signaling. Here, we show that FZD6 dimerizes and that the dimer interface of FZD6 is formed by the transmembrane α-helices four and five. Most importantly, we present the agonist-induced dissociation/re-association of a GPCR dimer through the use of live cell imaging techniques...
August 9, 2017: Nature Communications
https://www.readbyqxmd.com/read/28782472/canonical-microrna-matching-differs-greatly-across-groups-of-g-protein-coupled-receptor-mrnas
#19
Michael S Parker, Ambikaipakan Balasubramaniam, Floyd R Sallee, Steven L Parker
BACKGROUND: Heptahelical G protein coupled receptors (GPCRs) support numerous sensory and metabolic functions and differ considerably in levels of expression. GPCR protein levels should link to regulation of GPCR mRNAs by microRNAs (miRs), which might significantly depend on numbers, size and GC content of the canonical antisense matches in mRNAs. These parameters of GPCR mRNAs have not been studied in detail. METHODS: Canonical matching profiles of human GPCR mRNAs and miRs were examined using segments of 7-15 nucleotides in windows shifted by one position over the entire microRNA sequence...
August 4, 2017: MicroRNA
https://www.readbyqxmd.com/read/28779842/strategy-for-the-thermostabilization-of-an-agonist-bound-gpcr-coupled-to-a-g-protein
#20
Annette Strege, Byron Carpenter, Patricia C Edwards, Christopher G Tate
Structure determination of G protein-coupled receptors (GPCRs) in the inactive state bound to high-affinity antagonists has been very successful through the implementation of a number of protein engineering and crystallization strategies. However, the structure determination of GPCRs in their fully active state coupled to a G protein is still very challenging. Recently, mini-G proteins were developed, which recapitulate the coupling of a full heterotrimeric G protein to a GPCR despite being less than one-third of the size...
2017: Methods in Enzymology
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