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G coupled protein receptors

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https://www.readbyqxmd.com/read/28527568/evolution-of-nuclear-receptors-and-ligand-signaling-toward-a-soft-key-lock-model
#1
Guillaume Holzer, Gabriel V Markov, Vincent Laudet
Nuclear receptors (NRs) are a family of ligand-regulated transcription factors that modulate a wide variety of physiological functions in a ligand-dependent manner. The first NRs were discovered as receptors of well-known hormones such as 17β-estradiol, corticosteroids, or thyroid hormones. In these cases a direct activation of the receptor transcriptional activity by a very specific ligand, with nanomolar affinity, was demonstrated, providing a strong conceptual framework to understand the mechanism of action of these hormones...
2017: Current Topics in Developmental Biology
https://www.readbyqxmd.com/read/28526706/cardiac-hyporesponsiveness-in-severe-sepsis-is-associated-with-nitric-oxide-dependent-activation-of-g-protein-receptor-kinase
#2
Daniela Dal-Secco, Silvia DalBó, Natalia E S Lautherbach, Fábio N Gava, Mara Rubia Nunes Celes, Patricia Oliveira Benedet, Adriana H Souza, Juliana Akinaga, Vanessa Lima, Katiussia P Silva, Luiz Ricardo A Kiguti, Marcos A Rossi, Isis do Carmo Kettelhut, André Sampaio Pupo, Fernando Queiroz Cunha, Jamil Assreuy
G protein-coupled receptor kinase isoform 2 (GRK2) has a critical role in physiological and pharmacological responses to endogenous and exogenous substances. Sepsis causes an important cardiovascular dysfunction in which nitric oxide (NO) has a relevant role. The present study aimed to assess the putative effect of inducible NO synthase (NOS-2)-derived NO on the activity of GRK2 in the context of septic cardiac dysfunction. C57BL/6 mice were submitted to severe septic injury by cecal ligation and puncture (CLP)...
May 19, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/28526554/the-roles-of-orexins-in-sleep-wake-regulation
#3
REVIEW
Michihiro Mieda
Orexin A and orexin B are hypothalamic neuropeptides initially identified as endogenous ligands for two orphan G-protein coupled receptors (GPCRs). A deficiency of orexin signaling results in the sleep disorder narcolepsy-cataplexy in humans, dogs, and rodents, a sleep disorder characterized by excessive daytime sleepiness and cataplexy. Multiple approaches, including molecular genetic, electrophysiological, pharmacological, and neuroanatomical studies have suggested that orexins play critical roles in the maintenance of wakefulness by regulating the function of monoaminergic and cholinergic neurons that are implicated in the regulation of wakefulness...
May 16, 2017: Neuroscience Research
https://www.readbyqxmd.com/read/28526450/the-association-of-single-nucleotide-polymorphisms-in-the-oxytocin-receptor-and-g-protein-coupled-receptor-kinase-6-grk6-genes-with-oxytocin-dosing-requirements-and-labor-outcomes
#4
Chad A Grotegut, Emily Ngan, Melanie E Garrett, Marie Lynn Miranda, Allison E Ashley-Koch, Geeta K Swamy
BACKGROUND: Oxytocin is a potent uterotonic agent that is widely used for induction and augmentation of labor. Oxytocin has a narrow therapeutic index and the optimal dosing for any individual woman varies widely. OBJECTIVE: The objective of this study was to determine if genetic variation in the oxytocin receptor (OXTR) or in the gene encoding G protein-coupled receptor kinase 6 (GRK6), which regulates desensitization of the OXTR, could explain variation in oxytocin dosing and labor outcomes among women being induced near term...
May 16, 2017: American Journal of Obstetrics and Gynecology
https://www.readbyqxmd.com/read/28524918/urotensin-ii-peptidomimetic-incorporating-a-non-reducible-1-5-triazole-disulfide-bond-reveals-a-pseudo-irreversible-covalent-binding-mechanism-to-the-urotensin-g-protein-coupled-receptor
#5
Salvatore Pacifico, Aidan Kerckhoffs, Andrew J Fallow, Rachel E Foreman, Remo Guerrini, John McDonald, David G Lambert, Andrew G Jamieson
The urotensin-II receptor (UTR) is a class A GPCR that predominantly binds to the pleiotropic cyclic peptide urotensin-II (U-II). U-II is constrained by a disulfide bridge that induces a β-turn structure and binds pseudo-irreversibly to UTR and is believed to result in a structural rearrangement of the receptor. However, it is not well understood how U-II binds pseudo-irreversibly and the nature of the reorganization of the receptor that results in G-protein activation. Here we describe a series of U-II peptidomimetics incorporating a non-reducible disulfide bond structural surrogate to investigate the feasibility that native U-II binds to the G protein-coupled receptor through disulfide bond shuffling as a mechanism of covalent interaction...
May 19, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28524165/molecular-assembly-of-rhodopsin-with-g-protein-coupled-receptor-kinases
#6
Yuanzheng He, Xiang Gao, Devrishi Goswami, Li Hou, Kuntal Pal, Yanting Yin, Gongpu Zhao, Oliver P Ernst, Patrick Griffin, Karsten Melcher, H Eric Xu
G protein-coupled receptor kinases (GRKs) play pivotal roles in desensitizing GPCR signaling but little is known about how GRKs recognize and phosphorylate GPCRs due to the technical difficulties in detecting the highly dynamic GPCR/GRK interaction. By combining a genetic approach with multiple biochemical assays, we identified the key determinants for the assembly of the prototypical GPCR rhodopsin with its kinase GRK1. Our work reveals that the regulatory G-protein signaling homology (RH) domain of GRKs is the primary binding site to GPCRs and an active conformation of the GRK1 kinase domain is required for efficient interaction with rhodopsin...
May 19, 2017: Cell Research
https://www.readbyqxmd.com/read/28523097/similarity-and-substructure-based-development-of-%C3%AE-2-adrenergic-receptor-ligands-based-on-unusual-scaffolds
#7
Denis Schmidt, Jakub Gunera, Jillian G Baker, Peter Kolb
The β2-adrenergic receptor (β2AR) is a G protein-coupled receptor (GPCR) and a well-explored target. Here, we report the discovery of 13 ligands, ten of which are novel, of this particular GPCR. They have been identified by similarity- and substructure-based searches using multiple ligands, which were described in an earlier study, as starting points. Of note, two of the molecules used as queries here distinguish themselves from other β2AR antagonists by their unique scaffold. The molecules described in this work allow us to explore the ligand space around the previously reported molecules in greater detail, leading to insights into their structure-activity relationship...
May 11, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28522608/altered-learning-memory-and-social-behavior-in-type-1-taste-receptor-subunit-3-knockout-mice-is-associated-with-neuronal-dysfunction
#8
Bronwen Martin, Rui Wang, Wei-Na Cong, Caitlin M Daimon, Wells W Wu, Bin Ni, Kevin G Becker, Elin Lehrmann, William H Wood, Yongqing Zhang, Harmonie Etienne, Jaana van Gastel, Abdelkrim Azmi, Jonathan Janssens, Stuart Maudsley
The type 1 taste receptor member 3 (T1R3) is a G protein-coupled receptor (GPCR) involved in sweet taste perception. Besides the tongue, the T1R3 receptor is highly expressed in brain areas implicated in cognition, including the hippocampus and cortex. As cognitive decline is often preceded by significant metabolic or endocrinological dysfunctions, regulated by the sweet taste perception system, we hypothesized that a disruption of the sweet taste perception in the brain could have a key role in the development of cognitive dysfunction...
May 18, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28520140/towards-the-identification-of-novel-breast-cancer-inhibitors-specific-for-gper-expressing-cells
#9
Francescsa Aiello, Gabriele Carullo, Francesca Giordano, Elena Spina, Alessandra Nigro, Antonio Garofalo, Sabrina Tassini, Gabriele Costantino, Paolo Vincetti, Agostino Bruno, Marco Radi
Together with ERα/β, GPER (G protein-coupled estrogen receptor) mediates important pathophysiological signaling pathways induced by estrogens and is currently regarded as a promising target for ER-negative and triple-negative breast cancer. Only a few selective GPER modulators have been reported to date and their use in cancer cell lines has often led to contradictory results. Here we report the application of virtual screening and cell-based studies for the identification of new chemical scaffolds with a specific anti-proliferative effect against GPER-expressing breast cancer cell lines...
May 18, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28518143/calcium-sensing-receptor-protects-high-glucose-induced-energy-metabolism-disorder-via-blocking-gp78-ubiquitin-proteasome-pathway
#10
Yuehong Wang, Ping Gao, Can Wei, Hongzhu Li, Li Zhang, Yajun Zhao, Bo Wu, Ye Tian, Weihua Zhang, Lingyun Wu, Rui Wang, Changqing Xu
Diabetic cardiomyopathy (DCM) is a major complication and fatal cause of the patients with diabetes. The calcium sensing receptor (CaSR) is a G protein-coupled receptor, which is involved in maintaining calcium homeostasis, regulating cell proliferation and apoptosis, and so on. In our previous study, we found that CaSR expression, intracellular calcium levels and cardiac function were all significantly decreased in DCM rats; however, the exact mechanism are not clear yet. The present study revealed the protective role of CaSR in myocardial energy metabolism disorder induced by high glucose (HG) as well as the underlying mechanism...
May 18, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28516903/molecular-mechanism-of-g%C3%AE-i-activation-by-non-gpcr-proteins-with-a-g%C3%AE-binding-and-activating-motif
#11
Alain Ibáñez de Opakua, Kshitij Parag-Sharma, Vincent DiGiacomo, Nekane Merino, Anthony Leyme, Arthur Marivin, Maider Villate, Lien T Nguyen, Miguel Angel de la Cruz-Morcillo, Juan B Blanco-Canosa, Sekar Ramachandran, George S Baillie, Richard A Cerione, Francisco J Blanco, Mikel Garcia-Marcos
Heterotrimeric G proteins are quintessential signalling switches activated by nucleotide exchange on Gα. Although activation is predominantly carried out by G-protein-coupled receptors (GPCRs), non-receptor guanine-nucleotide exchange factors (GEFs) have emerged as critical signalling molecules and therapeutic targets. Here we characterize the molecular mechanism of G-protein activation by a family of non-receptor GEFs containing a Gα-binding and -activating (GBA) motif. We combine NMR spectroscopy, computational modelling and biochemistry to map changes in Gα caused by binding of GBA proteins with residue-level resolution...
May 18, 2017: Nature Communications
https://www.readbyqxmd.com/read/28516479/g%C3%AE-s-signalling-of-the-cb1-receptor-and-the-influence-of-receptor-number
#12
David B Finlay, Erin E Cawston, Natasha L Grimsey, Morag R Hunter, Anisha Korde, V Kiran Vemuri, Alexandros Makriyannis, Michelle Glass
BACKGROUND AND PURPOSE: CB1 cannabinoid receptor signalling is canonically mediated through inhibitory Gαi proteins, but signalling through other G proteins occurs under some circumstances; Gαs being the most characterised secondary pathway. Determinants of this signalling switch identified to date include Gαi blockade, CB1 /D2 dopamine receptor co-stimulation, CB1 agonist class, and cell background. The aim of this study was to examine the effects of receptor number and ligand dependence on CB1 signalling...
May 18, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28516266/constitutive-calcium-entry-and-cancer-updated-views-and-insights
#13
REVIEW
Olivier Mignen, Bruno Constantin, Marie Potier-Cartereau, Aubin Penna, Mathieu Gautier, Maxime Guéguinou, Yves Renaudineau, Kenji F Shoji, Romain Félix, Elsa Bayet, Paul Buscaglia, Marjolaine Debant, Aurélie Chantôme, Christophe Vandier
Tight control of basal cytosolic Ca(2+) concentration is essential for cell survival and to fine-tune Ca(2+)-dependent cell functions. A way to control this basal cytosolic Ca(2+) concentration is to regulate membrane Ca(2+) channels including store-operated Ca(2+) channels and secondary messenger-operated channels linked to G-protein-coupled or tyrosine kinase receptor activation. Orai, with or without its reticular STIM partner and Transient Receptor Potential (TRP) proteins, were considered to be the main Ca(2+) channels involved...
May 17, 2017: European Biophysics Journal: EBJ
https://www.readbyqxmd.com/read/28515494/ligand-chain-length-drives-activation-of-lipid-g-protein-coupled-receptors
#14
Anastassia Troupiotis-Tsaïlaki, Julian Zachmann, Inés González-Gil, Angel Gonzalez, Silvia Ortega-Gutiérrez, Maria L López-Rodríguez, Leonardo Pardo, Cedric Govaerts
Sphingosine-1-phosphate (S1P) is a lipid mediator that can activate five cell membrane G protein-coupled receptors (GPCRs) which carry a variety of essential functions and are promising drug targets. S1P is composed of a polar zwitterionic head-group and a hydrophobic alkyl chain. This implies an activation mechanism of its cognate receptor that must be significantly different from what is known for prototypical GPCRs (ie receptor to small hydrophilic ligands). Here we aim to identify the structural features responsible for S1P agonism by combining molecular dynamics simulations and functional assays using S1P analogs of different alkyl chain lengths...
May 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28515165/zinc-supplementation-via-gpr39-upregulates-pkc%C3%AE-to-protect-intestinal-barrier-integrity-in-caco-2-cells-challenged-by-salmonella-enterica-serovar-typhimurium
#15
Yu-Xin Shao, Zhao Lei, Patricia G Wolf, Yan Gao, Yu-Ming Guo, Bing-Kun Zhang
Background: Zinc has been shown to improve intestinal barrier function against Salmonella enterica serovar Typhimurium (S. typhimurium) infection, but the mechanisms involved in this process remain undefined.Objective: We aimed to explore the roles of G protein-coupled receptor (GPR)39 and protein kinase Cζ (PKCζ) in the regulation by zinc of intestinal barrier function.Methods: A Transwell Caco-2 monolayer was pretreated with 0, 50, or 100 μM Zn and then incubated with S. typhimurium for 0-6 h. Afterward, cells silenced by the small interfering RNA for GPR39 or PKCζ were pretreated with 100 μM Zn and incubated with S...
May 17, 2017: Journal of Nutrition
https://www.readbyqxmd.com/read/28515031/phenotypic-variability-in-a-family-with-acrodysostosis-type-2-caused-by-a-novel-pde4d-mutation-affecting-the-serine-target-of-pka-phosphorylation
#16
Julia Hoppmann, Julia Gesing, Caroline Silve, Chrystel Leroy, Astrid Bertsche, Franz Wolfgang Hirsch, Wieland Kiess, Roland Pfäffle, Volker Schuster
BACKGROUND: Acrodysostosis is a very rare congenital multisystem condition characterized by skeletal dysplasia with severe brachydactyly, midfacial hypoplasia, and short stature, varying degrees of intellectual disability, and possible resistance to multiple G protein-coupled receptor signalling hormones. Two distinct subtypes are differentiated: acrodysostosis type 1 resulting from defects in PRKAR1A and acrodysostosis type 2 caused by mutations in PDE4D. Most cases are sporadic. OBJECTIVE: We report on a rare multigenerational familial case of acrodysostosis type 2 due to a novel autosomal dominantly inherited PDE4D mutation...
May 17, 2017: Journal of Clinical Research in Pediatric Endocrinology
https://www.readbyqxmd.com/read/28514728/the-g-protein-coupled-bile-acid-receptor-gpbar1-tgr5-protects-against-renal-inflammation-and-renal-cancer-cell-proliferation-and-migration-through-antagonizing-nf-%C3%AE%C2%BAb-and-stat3-signaling-pathways
#17
Jia Su, Qiqi Zhang, Hui Qi, Linlin Wu, Yuanqiang Li, Donna Yu, Wendong Huang, Wei-Dong Chen, Yan-Dong Wang
Gpbar1 (TGR5), a G-protein-coupled bile acid membrane receptor, is well known for its roles in regulation of glucose metabolism and energy homeostasis. In the current work, we found that TGR5 activation by its ligand suppressed lipopolysaccharide (LPS)-induced proinflammatory gene expression in wild-type (WT) but not TGR5-/- mouse kidney. Furthermore, we found that TGR5 is a suppressor of kidney cancer cell proliferation and migration. We show that TGR5 activation antagonized NF-κB and STAT3 signaling pathways through suppressing the phosphorylation of IκBα, the translocation of p65 and the phosphorylation of STAT3...
April 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28514451/structure-of-the-full-length-glucagon-class-b-g-protein-coupled-receptor
#18
Haonan Zhang, Anna Qiao, Dehua Yang, Linlin Yang, Antao Dai, Chris de Graaf, Steffen Reedtz-Runge, Venkatasubramanian Dharmarajan, Hui Zhang, Gye Won Han, Thomas D Grant, Raymond G Sierra, Uwe Weierstall, Garrett Nelson, Wei Liu, Yanhong Wu, Limin Ma, Xiaoqing Cai, Guangyao Lin, Xiaoai Wu, Zhi Geng, Yuhui Dong, Gaojie Song, Patrick R Griffin, Jesper Lau, Vadim Cherezov, Huaiyu Yang, Michael A Hanson, Raymond C Stevens, Qiang Zhao, Hualiang Jiang, Ming-Wei Wang, Beili Wu
The human glucagon receptor, GCGR, belongs to the class B G-protein-coupled receptor family and plays a key role in glucose homeostasis and the pathophysiology of type 2 diabetes. Here we report the 3.0 Å crystal structure of full-length GCGR containing both the extracellular domain and transmembrane domain in an inactive conformation. The two domains are connected by a 12-residue segment termed the stalk, which adopts a β-strand conformation, instead of forming an α-helix as observed in the previously solved structure of the GCGR transmembrane domain...
May 17, 2017: Nature
https://www.readbyqxmd.com/read/28514449/human-glp-1-receptor-transmembrane-domain-structure-in-complex-with-allosteric-modulators
#19
Gaojie Song, Dehua Yang, Yuxia Wang, Chris de Graaf, Qingtong Zhou, Shanshan Jiang, Kaiwen Liu, Xiaoqing Cai, Antao Dai, Guangyao Lin, Dongsheng Liu, Fan Wu, Yiran Wu, Suwen Zhao, Li Ye, Gye Won Han, Jesper Lau, Beili Wu, Michael A Hanson, Zhi-Jie Liu, Ming-Wei Wang, Raymond C Stevens
The glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR) are members of the secretin-like class B family of G-protein-coupled receptors (GPCRs) and have opposing physiological roles in insulin release and glucose homeostasis. The treatment of type 2 diabetes requires positive modulation of GLP-1R to inhibit glucagon secretion and stimulate insulin secretion in a glucose-dependent manner. Here we report crystal structures of the human GLP-1R transmembrane domain in complex with two different negative allosteric modulators, PF-06372222 and NNC0640, at 2...
May 17, 2017: Nature
https://www.readbyqxmd.com/read/28513578/crystal-structure-of-a-multi-domain-human-smoothened-receptor-in-complex-with-a-super-stabilizing-ligand
#20
Xianjun Zhang, Fei Zhao, Yiran Wu, Jun Yang, Gye Won Han, Suwen Zhao, Andrii Ishchenko, Lintao Ye, Xi Lin, Kang Ding, Venkatasubramanian Dharmarajan, Patrick R Griffin, Cornelius Gati, Garrett Nelson, Mark S Hunter, Michael A Hanson, Vadim Cherezov, Raymond C Stevens, Wenfu Tan, Houchao Tao, Fei Xu
The Smoothened receptor (SMO) belongs to the Class Frizzled of the G protein-coupled receptor (GPCR) superfamily, constituting a key component of the Hedgehog signalling pathway. Here we report the crystal structure of the multi-domain human SMO, bound and stabilized by a designed tool ligand TC114, using an X-ray free-electron laser source at 2.9 Å. The structure reveals a precise arrangement of three distinct domains: a seven-transmembrane helices domain (TMD), a hinge domain (HD) and an intact extracellular cysteine-rich domain (CRD)...
May 17, 2017: Nature Communications
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