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https://www.readbyqxmd.com/read/28449310/rational-design-of-nanobody80-loop-peptidomimetics-towards-biased-%C3%AE-2-adrenergic-receptor-ligands
#1
Charlotte Martin, Samuel Moors, Mia Danielsen, Cecilia Betti, Cecilia Fabris, Daniel Sejer Pedersen, Els Pardon, Marion Peyressatre, Krisztina Fehér, Jose C Martins, Jesper Mosolff Mathiesen, May Morris, Nick Devoogdt, Vicky Caveliers, Frank De Proft, Jan Steyaert, Steven Ballet
G protein-coupled receptors (GPCRs) play an important role for many cellular responses, and as such their mechanism of action is of utmost interest. To gain insight into the active conformation of GPCRs, the X-ray crystal structures of Nanobody(Nb)-stabilized β2-adrenergic receptor (β2AR) have been reported. Nb80 in particular is able to bind the intracellular G protein binding site of β2AR and stabilize the receptors in an active conformation. Within Nb80, the complementarity-determining region 3 (CDR3) is responsible for most of the binding interactions...
April 27, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28448853/a-cluster-of-aspartic-residues-in-the-extracellular-loop-ii-of-par-4-is-important-for-thrombin-interaction-and-activation-of-platelets
#2
Daniel Sánchez Centellas, Sushanth Gudlur, Alejandro Vicente-Carrillo, Sofia Ramström, Tomas L Lindahl
Thrombin activates platelets via proteolytic cleavage of protease-activated receptors (PARs) 1 and 4. The two PARs have distinct but complementary roles. The mechanisms responsible for PAR1 activation by thrombin have been extensively studied. However, much less is known regarding thrombin activation of PAR4, especially the potential involvement of regions of PAR4 other than the N-terminal, which is bound to the catalytic site of thrombin. We have studied PAR4 in S. cerevisiae strain MMY12, an expression system in which the GPCR receptors are connected to a Lac Z reporter gene resulting in increased β-galactosidase activity...
April 13, 2017: Thrombosis Research
https://www.readbyqxmd.com/read/28448471/regulation-of-g-protein-coupled-receptors-by-ubiquitination
#3
REVIEW
Kamila Skieterska, Pieter Rondou, Kathleen Van Craenenbroeck
G protein-coupled receptors (GPCRs) comprise the largest family of membrane receptors that control many cellular processes and consequently often serve as drug targets. These receptors undergo a strict regulation by mechanisms such as internalization and desensitization, which are strongly influenced by posttranslational modifications. Ubiquitination is a posttranslational modification with a broad range of functions that is currently gaining increased appreciation as a regulator of GPCR activity. The role of ubiquitination in directing GPCRs for lysosomal degradation has already been well-established...
April 27, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28448021/detection-of-ligand-activated-g-protein-coupled-receptor-internalization-by-confocal-microscopy
#4
Jingwen Yang, Yunjun Yan, Xiaowei Xiang, Yuchao Xu, Naiming Zhou, Tianming Wang
Confocal laser scanning microscopy (CLSM) is an optical imaging technique for high-contrast imaging. It is a powerful approach to visualize fluorescent fusion proteins, such as green fluorescent protein (GFP), to determine their expression, localization, and function. The subcellular localization of target proteins is important for identification, characterization, and functional analyses. Internalization is one of the predominant mechanisms controlling G protein-coupled receptor (GPCR) signaling to ensure the appropriate cellular responses to stimuli...
April 9, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28442638/deep-sequencing-of-the-transcriptome-in-the-anterior-pituitary-of-heifers-before-and-after-ovulation
#5
Kiran Pandey, Yoichi Mizukami, Kenji Watanabe, Syuiti Sakaguti, Hiroya Kadokawa
We aimed to determine gene expression patterns in the anterior pituitary (AP) of heifers before and after ovulation via deep sequencing of the transcriptome (RNA-seq) to identify new genes and clarify important pathways. Heifers were slaughtered on the estrus day (pre-ovulation; n=5) or 3 days after ovulation (post-ovulation; n=5) for AP collection. We randomly selected 4 pre-ovulation and 4 post-ovulation APs, and the ribosomal RNA-depleted poly (A)+RNA were prepared to assemble next-generation sequencing libraries...
April 23, 2017: Journal of Veterinary Medical Science
https://www.readbyqxmd.com/read/28442430/design-and-purification-of-active-truncated-phosphoinositide-3-kinase-gamma-protein-constructs-for-structural-studies
#6
A Vujičić Žagar, L Scapozza, O Vadas
Phosphoinositide 3-kinase gamma (PI3Kγ) is a lipid kinase that plays a crucial role in cell migration, chemotaxis, oxidative burst and myocardial contractility. It is activated downstream of G protein-coupled receptors (GPCRs) and small GTPases of Ras superfamily. PI3Kγ is a heterodimer composed of a catalytic and a regulatory subunit that is expressed mostly in hematopoietic cells and in the heart. Although it has attracted a lot of attention because of its link with tumor inflammation and heart diseases, its regulation is still not fully understood...
April 22, 2017: Protein Expression and Purification
https://www.readbyqxmd.com/read/28439254/distinct-conformational-dynamics-of-three-g-protein-coupled-receptors-measured-using-flash-bret-biosensors
#7
Kyla Bourque, Darlaine Pétrin, Rory Sleno, Dominic Devost, Alice Zhang, Terence E Hébert
A number of studies have profiled G protein-coupled receptor (GPCR) conformation using fluorescent biaresenical hairpin binders (FlAsH) as acceptors for BRET or FRET. These conformation-sensitive biosensors allow reporting of movements occurring on the intracellular surface of a receptor to investigate mechanisms of receptor activation and function. Here, we generated eight FlAsH-BRET-based biosensors within the sequence of the β2-adrenergic receptor (β2AR) and compared agonist-induced responses to the angiotensin II receptor type I (AT1R) and the prostaglandin F2α receptor (FP)...
2017: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/28439124/characterisation-of-a-cell-free-synthesised-g-protein-coupled-receptor
#8
Patrick J Shilling, Fabian Bumbak, Daniel J Scott, Ross A D Bathgate, Paul R Gooley
G-protein coupled receptors are the largest family of integral membrane proteins found within the human genome. They function as receptors and modulators to a wide range of ligands and responses which are crucial for human health. GPCR study, specifically the investigation of structure and interaction to cognate ligands, is of high priority. Limitations for structural study can be traced in part, to obtaining suitable quantities of recombinant protein. We sought to address the limitations of traditional recombinant technologies by utilising an Escherichia coli based cell-free protein synthesis (CFPS) approach for production of a thermostable neurotensin receptor 1 (en2NTS1)...
April 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28438833/g-protein-gi1-exhibits-basal-coupling-but-not-preassembly-with-g-protein-coupled-receptors
#9
Alexey Bondar, Josef Lazar
The Gi/o protein family transduces signals from a diverse group of G protein-coupled receptors (GPCRs). The observed specificity of Gi/o-GPCR coupling and high rate of Gi/o signal transduction have been hypothesized to be enabled by existence of stable associates between Gi/o proteins and their cognate GPCRs in the inactive state (Gi/o-GPCR preassembly). To test this hypothesis, we applied the recently developed technique of two-photon polarization microscopy (2PPM) to Gαi1 subunits labeled with fluorescent proteins and four GPCRs (the α2A-adrenergic receptor (α2A-AR), γ-aminobutyric acid receptor B (GABAB), cannabinoid receptor type 1 (CB1R) and dopamine receptor type 2 (D2R))...
April 24, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28437792/phase-plate-cryo-em-structure-of-a-class-b-gpcr-g-protein-complex
#10
Yi-Lynn Liang, Maryam Khoshouei, Mazdak Radjainia, Yan Zhang, Alisa Glukhova, Jeffrey Tarrasch, David M Thal, Sebastian G B Furness, George Christopoulos, Thomas Coudrat, Radostin Danev, Wolfgang Baumeister, Laurence J Miller, Arthur Christopoulos, Brian K Kobilka, Denise Wootten, Georgios Skiniotis, Patrick M Sexton
Class B G-protein-coupled receptors are major targets for the treatment of chronic diseases, such as osteoporosis, diabetes and obesity. Here we report the structure of a full-length class B receptor, the calcitonin receptor, in complex with peptide ligand and heterotrimeric Gαsβγ protein determined by Volta phase-plate single-particle cryo-electron microscopy. The peptide agonist engages the receptor by binding to an extended hydrophobic pocket facilitated by the large outward movement of the extracellular ends of transmembrane helices 6 and 7...
April 24, 2017: Nature
https://www.readbyqxmd.com/read/28434782/dimeric-isoxazolyl-1-4-dihydropyridines-have-enhanced-binding-at-the-multi-drug-resistance-transporter
#11
Scott A Steiger, Chun Li, Donald S Backos, Philip Reigan, N R Natale
A series of dimeric isoxazolyl-1,4-dihydropyridines (IDHPs) were prepared by click chemistry and examined for their ability to bind the multi-drug resistance transporter (MDR-1), a member of the ATP-binding cassette superfamily (ABC). Eight compounds in the present study exhibited single digit micromolar binding to this efflux transporter. One monomeric IDHP m-Br-1c, possessed submicromolar binding of 510nM at MDR-1. Three of the dimeric IDHPs possessed <1.5µM activity, and 4b and 4c were observed to have superior binding selectivity compared to their corresponding monomers verses the voltage gated calcium channel (VGCC)...
April 8, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28432958/membrane-fusion-between-baculovirus-budded-virus-enveloped-particles-and-giant-liposomes-generated-using-a-droplet-transfer-method-for-the-incorporation-of-recombinant-membrane-proteins
#12
Misako Nishigami, Takaaki Mori, Masahiro Tomita, Kingo Takiguchi, Kanta Tsumoto
Giant proteoliposomes are generally useful as artificial cell membranes in biochemical and biophysical studies, and various procedures for their preparation have been reported. We present here a novel preparation technique that involves the combination of i) cell-sized lipid vesicles (giant unilamellar vesicles, GUVs) that are generated using the droplet-transfer method, where lipid monolayer-coated water-in-oil microemulsion droplets interact with oil/water interfaces to form enclosed bilayer vesicles, and ii) budded viruses (BVs) of baculovirus (Autographa californica nucleopolyhedrovirus) that express recombinant transmembrane proteins on their envelopes...
April 13, 2017: Colloids and Surfaces. B, Biointerfaces
https://www.readbyqxmd.com/read/28431242/structural-and-functional-analysis-of-a-%C3%AE-2-adrenergic-receptor-complex-with-grk5
#13
Konstantin E Komolov, Yang Du, Nguyen Minh Duc, Robin M Betz, João P G L M Rodrigues, Ryan D Leib, Dhabaleswar Patra, Georgios Skiniotis, Christopher M Adams, Ron O Dror, Ka Young Chung, Brian K Kobilka, Jeffrey L Benovic
The phosphorylation of agonist-occupied G-protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) functions to turn off G-protein signaling and turn on arrestin-mediated signaling. While a structural understanding of GPCR/G-protein and GPCR/arrestin complexes has emerged in recent years, the molecular architecture of a GPCR/GRK complex remains poorly defined. We used a comprehensive integrated approach of cross-linking, hydrogen-deuterium exchange mass spectrometry (MS), electron microscopy, mutagenesis, molecular dynamics simulations, and computational docking to analyze GRK5 interaction with the β2-adrenergic receptor (β2AR)...
April 20, 2017: Cell
https://www.readbyqxmd.com/read/28427097/systematic-quantification-of-gpcr-camp-controlled-protein-kinase-a-interactions
#14
O Torres-Quesada, R Röck, E Stefan
The diffusible second messenger cyclic AMP (cAMP) originates from multiple G protein-coupled receptor (GPCR) cascades activating the intracellular key effector protein kinase A (PKA). Spatially and temporally restricted cAMP-fluxes are directly sensed by macromolecular PKA complexes. The consequences are alterations of molecular interactions, which lead to activation of compartmentalized PKA phosphotransferase activities, regulating a vast array of cellular functions. To decode cell-type and cell-compartment specific PKA functions, the spatio-temporal dynamics of small molecule:protein interactions, protein:protein interactions (PPIs), cAMP-mobilization, and phosphotransferase activities need to be determined directly in the appropriate cellular context...
April 2017: Hormone and Metabolic Research, Hormon- und Stoffwechselforschung, Hormones et Métabolisme
https://www.readbyqxmd.com/read/28424220/gababr-induced-egfr-transactivation-promotes-migration-of-human-prostate-cancer-cells
#15
Shuai Xia, Cong He, Yini Zhu, Suyun Wang, Huiping Li, Zhongling Zhang, Xinnong Jiang, Jianfeng Liu
G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) act in concert to regulate cell growth, proliferation, survival, and migration. Metabotropic GABAB receptor (GABABR) is the GPCR for the main inhibitory neurotransmitter GABA in the central nervous system. Increased expression of GABABR has been detected in human cancer tissues and cancer cell lines, but the role of GABABR in these cells is controversial and the underlying mechanism remains poorly understood. Here, we investigated whether GABABR hijacks RTK signaling to modulate the fates of human prostate cancer cells...
April 19, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28422162/a-comparative-analysis-of-human-and-mouse-islet-g-protein-coupled-receptor-expression
#16
Stefan Amisten, Patricio Atanes, Ross Hawkes, Inmaculada Ruz-Maldonado, Bo Liu, Fariborz Parandeh, Min Zhao, Guo Cai Huang, Albert Salehi, Shanta J Persaud
G-protein coupled receptors (GPCRs) are essential for islet function, but most studies use rodent islets due to limited human islet availability. We have systematically compared the GPCR mRNA expression in human and mouse islets to determine to what extent mouse islets can be used as surrogates for human islets to study islet GPCR function, and we have identified species-specific expression of several GPCRs. The A3 receptor (ADORA3) was expressed only in mouse islets and the A3 agonist MRS 5698 inhibited glucose-induced insulin secretion from mouse islets, with no effect on human islets...
April 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28421075/activation-of-adhesion-gpcr-emr2-adgre2-induces-macrophage-differentiation-and-inflammatory-responses-via-g%C3%AE-16-akt-mapk-nf-%C3%AE%C2%BAb-signaling-pathways
#17
Kuan-Yu I, Yi-Shu Huang, Ching-Hsun Hu, Wen-Yi Tseng, Chia-Hsin Cheng, Martin Stacey, Siamon Gordon, Gin-Wen Chang, Hsi-Hsien Lin
EMR2/ADGRE2 is a human myeloid-restricted adhesion G protein-coupled receptor critically implicated in vibratory urticaria, a rare type of allergy caused by vibration-induced mast cell activation. In addition, EMR2 is also highly expressed by monocyte/macrophages and has been linked to neutrophil migration and activation. Despite these findings, little is known of EMR2-mediated signaling and its role in myeloid biology. In this report, we show that activation of EMR2 via a receptor-specific monoclonal antibody promotes the differentiation of human THP-1 monocytic cell line and induces the expression of pro-inflammatory mediators, including IL-8, TNF-α, and MMP-9...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28417881/understanding-gpcr-signaling-in-the-brain-the-path-to-cns-drug-discovery
#18
EDITORIAL
David Chatenet, Terence E Hébert
No abstract text is available yet for this article.
February 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28416805/a-new-inhibitor-of-the-%C3%AE-arrestin-ap2-endocytic-complex-reveals-interplay-between-gpcr-internalization-and-signalling
#19
Alexandre Beautrait, Justine S Paradis, Brandon Zimmerman, Jenna Giubilaro, Ljiljana Nikolajev, Sylvain Armando, Hiroyuki Kobayashi, Lama Yamani, Yoon Namkung, Franziska M Heydenreich, Etienne Khoury, Martin Audet, Philippe P Roux, Dmitry B Veprintsev, Stéphane A Laporte, Michel Bouvier
In addition to G protein-coupled receptor (GPCR) desensitization and endocytosis, β-arrestin recruitment to ligand-stimulated GPCRs promotes non-canonical signalling cascades. Distinguishing the respective contributions of β-arrestin recruitment to the receptor and β-arrestin-promoted endocytosis in propagating receptor signalling has been limited by the lack of selective analytical tools. Here, using a combination of virtual screening and cell-based assays, we have identified a small molecule that selectively inhibits the interaction between β-arrestin and the β2-adaptin subunit of the clathrin adaptor protein AP2 without interfering with the formation of receptor/β-arrestin complexes...
April 18, 2017: Nature Communications
https://www.readbyqxmd.com/read/28412414/endothelin-1-promotes-hypertrophic-remodelling-of-cardiac-myocytes-by-activating-sustained-signalling-and-transcription-downstream-of-endothelin-type-a-receptors
#20
Caroline R Archer, Emma L Robinson, Faye M Drawnel, H Llewelyn Roderick
G-protein coupled receptor (GPCR) mediated activation of the MAPK signalling cascade is a key pathway in the induction of hypertrophic remodelling of the heart - a response to pathological cues including hypertension and myocardial infarction. While levels of pro-hypertrophic hormone agonists of GPCRs increase during periods of greater workload to enhance cardiac output, hypertrophy does not necessarily result. Here we investigated the relationship between the duration of exposure to the pro-hypertrophic GPCR agonist endothelin-1 (ET-1) and the induction of hypertrophic remodelling in neonatal rat ventricular myocytes (NRVM) and in the adult rat heart in vivo...
April 13, 2017: Cellular Signalling
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