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Lipid gpcr

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https://www.readbyqxmd.com/read/28231433/discovery-of-a-potent-and-selective-sphingosine-kinase-1-inhibitor-through-the-molecular-combination-of-chemotype-distinct-screening-hits
#1
Mark E Schnute, Matthew D McReynolds, Jeffrey Carroll, Jill E Chrencik, Maureen K Highkin, Kaliapan Iyanar, Gina Jerome, John W Rains, Matthew Saabye, Jeffrey A Scholten, Matthew Yates, Marek M Nagiec
Sphingosine kinase (SphK) is the major source of the lipid mediator and GPCR agonist sphingosine-1-phosphate (S1P). S1P promotes cell growth, survival and migration and is a key regulator of lymphocyte trafficking. Inhibition of S1P signaling has been proposed as a strategy for treatment of inflammatory diseases and cancer. Two different formats of an enzyme based high-throughput screen yielded two attractive chemotypes capable of inhibiting S1P formation in cells. The molecular combination of these screening hits led to compound 22a (PF-543) with two orders of magnitude improved potency...
February 23, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28218648/expression-purification-and-monitoring-of-conformational-changes-of-hcb2-tmh67h8-in-different-membrane-mimetic-lipid-mixtures-using-circular-dichroism-and-nmr-techniques
#2
Elvis K Tiburu, Jianqin Zhuang, Heidimarie N A Fleischer, Patrick K Arthur, Gordon A Awandare
This work was intended to develop self-assembly lipids for incorporating G-protein coupled receptors (GPCRs) in order to improve the success rate for nuclear magnetic resonance spectroscopy (NMR) structural elucidation. We hereby report the expression and purification of uniformly (15)N-labeled human cannabinoid receptor-2 domain in insect cell media. The domain was refolded by screening several membrane mimetic environments. Different q ratios of isotropic bicelles were screened for solubilizing transmembrane helix 6, 7 and 8 (TMH67H8)...
February 17, 2017: Membranes
https://www.readbyqxmd.com/read/28209512/n-glycan-dependent-cell-surface-expression-of-the-p2y2-receptor-and-n-glycan-independent-distribution-to-lipid-rafts
#3
Tetsuto Nakagawa, Chihiro Takahashi, Hitomi Matsuzaki, Shohei Takeyama, Shinpei Sato, Ayaka Sato, Yoshiyuki Kuroda, Hideyoshi Higashi
P2Y2 receptor (P2Y2R) is a G-protein-coupled receptor (GPCR) that couples with Gαq/11 and is stimulated by ATP and UTP. P2Y2R is involved in pain, proinflammatory changes, and blood pressure control. Some GPCRs are localized in lipid rafts for interaction with other signaling molecules. In this study, we prepared N-glycan-deficient mutants by mutating the two consensus Asn residues for N-glycosylation to Gln to examine intracellular localization and association with lipid rafts. Western blotting of the wild type (WT) protein and mutants (N9Q, N13Q, N9Q/N13Q) in COS-7 cells showed that both Asn residues were glycosylated in the WT...
February 14, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28159877/g-protein-coupled-receptor-signaling-in-cilia
#4
Kirk Mykytyn, Candice Askwith
G-protein-coupled receptors (GPCRs) are the largest and most versatile family of signaling receptors in humans. They respond to diverse external signals, such as photons, proteins, peptides, chemicals, hormones, lipids, and sugars, and mediate a myriad of functions in the human body. Signaling through GPCRs can be optimized by enriching receptors and downstream effectors in discrete cellular domains. Many GPCRs have been found to be selectively targeted to cilia on numerous mammalian cell types. Moreover, investigations into the pathophysiology of human ciliopathies have implicated GPCR ciliary signaling in a number of developmental and cellular pathways...
February 3, 2017: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/28112925/highly-potent-non-carboxylic-acid-autotaxin-inhibitors-reduce-melanoma-metastasis-and-chemotherapeutic-resistance-of-breast-cancer-stem-cells
#5
Souvik Banerjee, Derek D Norman, Sue Chin Lee, Abby L Parrill, Truc Chi T Pham, Daniel L Baker, Gabor J Tigyi, Duane D Miller
Autotaxin (ATX, aka. ENPP2) is the main source of the lipid mediator lysophosphatidic acid (LPA) in biological fluids. This study reports on inhibitors of ATX derived by lead optimization of the benzene-sulfonamide in silico hit compound 3. The new analogues provide a comprehensive structure-activity relationship of the benzene-sulfonamide scaffold that yielded a series of highly potent ATX inhibitors. The three most potent analogues (3a, IC50 ∼ 32 nM; 3b, IC50 ∼ 9 nM; and 14, IC50 ∼ 35 nM) inhibit ATX-dependent invasion of A2058 human melanoma cells in vitro...
February 10, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28073248/interplay-of-g-protein-coupled-receptors-with-the-membrane-insights-from-supra-atomic-coarse-grain-molecular-dynamics-simulations
#6
Xavier Periole
G protein-coupled receptors (GPCRs) are central to many fundamental cellular signaling pathways. They transduce signals from the outside to the inside of cells in physiological processes ranging from vision to immune response. It is extremely challenging to look at them individually using conventional experimental techniques. Recently, a pseudo atomistic molecular model has emerged as a valuable tool to access information on GPCRs, more specifically on their interactions with their environment in their native cell membrane and the consequences on their supramolecular organization...
January 11, 2017: Chemical Reviews
https://www.readbyqxmd.com/read/27936598/effect-of-n-terminal-myristoylation-on-the-active-conformation-of-g%C3%AE-i1-gtp
#7
Siri C van Keulen, Ursula Rothlisberger
G proteins are part of the G-protein-coupled receptor (GPCR) signal transduction cascade in which they transfer a signal from the membrane-embedded GPCR to other proteins in the cell. In the case of the inhibitory G-protein heterotrimer, permanent N-terminal myristoylation can transiently localize the Gαi subunit at the membrane as well as crucially influence Gαi's function in the GTP-bound conformation. The attachment of lipids to proteins is known to be essential for membrane trafficking; however, our results suggest that lipidation is also important for protein-protein interactions during signal transduction...
December 29, 2016: Biochemistry
https://www.readbyqxmd.com/read/27935256/pigment-translocation-in-caridean-shrimp-chromatophores-receptor-type-signal-transduction-second-messengers-and-cross-talk-among-multiple-signaling-cascades
#8
Sarah Ribeiro Milograna, Márcia Regina Ribeiro, Fernanda Tinti Bell, John Campbell McNamara
Pigment aggregation in shrimp chromatophores is triggered by red pigment concentrating hormone (RPCH), a neurosecretory peptide whose plasma membrane receptor may be a G-protein coupled receptor (GPCR). While RPCH binding activates the Ca(2+) /cGMP signaling cascades, a role for cyclic AMP (cAMP) in pigment aggregation is obscure, as are the steps governing Ca(2+) release from the smooth endoplasmic reticulum (SER). A role for the antagonistic neuropeptide, pigment dispersing homone (α-PDH) is also unclear...
November 2016: Journal of Experimental Zoology. Part A, Ecological Genetics and Physiology
https://www.readbyqxmd.com/read/27923683/role-of-a-tachykinin-related-peptide-and-its-receptor-in-modulating-the-olfactory-sensitivity-in-the-oriental-fruit-fly-bactrocera-dorsalis-hendel
#9
Shun-Hua Gui, Hong-Bo Jiang, Li Xu, Yu-Xia Pei, Xiao-Qiang Liu, Guy Smagghe, Jin-Jun Wang
Insect tachykinin-related peptide (TRP), an ortholog of tachykinin in vertebrates, has been linked with regulation of diverse physiological processes, such as olfactory perception, locomotion, aggression, lipid metabolism and myotropic activity. In this study, we investigated the function of TRP (BdTRP) and its receptor (BdTRPR) in an important agricultural pest, the oriental fruit fly Bactrocera dorsalis. BdTRPR is a typical G-protein coupled-receptor (GPCR), and it could be activated by the putative BdTRP mature peptides with the effective concentrations (EC50) at the nanomolar range when expressed in Chinese hamster ovary cells...
January 2017: Insect Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/27906555/ligand-biased-regulation-of-ptdins-3-4-5-p3-dependent-signal-transduction-in-gpcr-control-of-pituitary-hormone-release
#10
Joshua G Pemberton, John P Chang
Biased signaling describes the selective activation of signal transduction cascades by structurally-related ligands downstream of shared G protein-coupled receptors (GPCRs). Although class I phosphoinositide 3-kinases (PI3Ks) are important components of GPCR-controlled transduction networks, little is known regarding the potential for biased regulation of class I PI3K-dependent signaling. The full compliment of class I PI3K catalytic subunits (p110α, p110β, p110δ and p110γ) first appear in bony fishes and, despite being associated with distinct cellular functions, all class I PI3Ks produce the lipid second-messenger phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3)...
December 1, 2016: Endocrinology
https://www.readbyqxmd.com/read/27864940/endogenous-lysophosphatidic-acid-lpa1-receptor-agonists-demonstrate-ligand-bias-between-calcium-and-erk-signalling-pathways-in-human-lung-fibroblasts
#11
Afrah Sattikar, Mark R Dowling, Elizabeth M Rosethorne
BACKGROUND AND PURPOSE: Human lung fibroblasts (HLF) express high levels of the LPA1 receptor, a GPCR that responds to the endogenous lipid mediator, lysophosphatidic acid (LPA). Several molecular species or analogues of LPA exist and have been detected in biological fluids such as serum and plasma. The most widely expressed of the LPA receptor family is the LPA1 receptor, which predominantly couples to Gq/11 , Gi/o and G12/13 proteins. This promiscuity of coupling raises the possibility that some of the LPA analogues may bias the LPA1 receptor towards one signalling pathway over another...
February 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/27851727/high-resolution-crystal-structure-of-the-human-cb1-cannabinoid-receptor
#12
Zhenhua Shao, Jie Yin, Karen Chapman, Magdalena Grzemska, Lindsay Clark, Junmei Wang, Daniel M Rosenbaum
The human cannabinoid G-protein-coupled receptors (GPCRs) CB1 and CB2 mediate the functional responses to the endocannabinoids anandamide and 2-arachidonyl glycerol (2-AG), as well as the widely consumed plant (phyto)cannabinoid Δ(9)-tetrahydrocannabinol (THC)(1). The cannabinoid receptors have been the targets of intensive drug discovery efforts owing to the therapeutic potential of modulators for controlling pain(2), epilepsy(3), obesity(4), and other maladies. Although much progress has recently been made in understanding the biophysical properties of GPCRs, investigations of the molecular mechanisms of the cannabinoids and their receptors have lacked high-resolution structural data...
November 16, 2016: Nature
https://www.readbyqxmd.com/read/27832814/obesity-induced-cardiac-lipid-accumulation-in-adult-mice-is-modulated-by-g-protein-coupled-receptor-kinase-2-levels
#13
Elisa Lucas, Rocio Vila-Bedmar, Alba C Arcones, Marta Cruces-Sande, Victoria Cachofeiro, Federico Mayor, Cristina Murga
BACKGROUND: The leading cause of death among the obese population is heart failure and stroke prompted by structural and functional changes in the heart. The molecular mechanisms that underlie obesity-related cardiac remodeling are complex, and include hemodynamic and metabolic alterations that ultimately affect the functionality of the myocardium. G protein-coupled receptor kinase 2 (GRK2) is an ubiquitous kinase able to desensitize the active form of several G protein-coupled receptors (GPCR) and is known to play an important role in cardiac GPCR modulation...
10, 2016: Cardiovascular Diabetology
https://www.readbyqxmd.com/read/27832490/adhesion-gpcrs-as-a-putative-class-of-metabotropic-mechanosensors
#14
Nicole Scholz, Kelly R Monk, Robert J Kittel, Tobias Langenhan
Adhesion GPCRs as mechanosensors. Different aGPCR homologs and their cognate ligands have been described in settings, which suggest that they function in a mechanosensory capacity. For details, see text G protein-coupled receptors (GPCRs) constitute the most versatile superfamily of biosensors. This group of receptors is formed by hundreds of GPCRs, each of which is tuned to the perception of a specific set of stimuli a cell may encounter emanating from the outside world or from internal sources. Most GPCRs are receptive for chemical compounds such as peptides, proteins, lipids, nucleotides, sugars, and other organic compounds, and this capacity is utilized in several sensory organs to initiate visual, olfactory, gustatory, or endocrine signals...
2016: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/27826255/membrane-mediated-oligomerization-of-g-protein-coupled-receptors-and-its-implications-for-gpcr-function
#15
REVIEW
Stefan Gahbauer, Rainer A Böckmann
The dimerization or even oligomerization of G protein coupled receptors (GPCRs) causes ongoing, controversial debates about its functional role and the coupled biophysical, biochemical or biomedical implications. A continously growing number of studies hints to a relation between oligomerization and function of GPCRs and strengthens the assumption that receptor assembly plays a key role in the regulation of protein function. Additionally, progress in the structural analysis of GPCR-G protein and GPCR-ligand interactions allows to distinguish between actively functional and non-signaling complexes...
2016: Frontiers in Physiology
https://www.readbyqxmd.com/read/27824122/real-time-monitoring-of-membrane-gpcr-reconstitution-by-plasmon-waveguide-resonance-on-the-role-of-lipids
#16
Pierre Calmet, Monica De Maria, Etienne Harté, Daniel Lamb, Maria Serrano-Vega, Ali Jazayeri, Nuska Tschammer, Isabel D Alves
G-protein coupled receptors (GPCRs) are important therapeutic targets since more than 40% of the drugs on the market exert their action through these proteins. To decipher the molecular mechanisms of activation and signaling, GPCRs often need to be isolated and reconstituted from a detergent-solubilized state into a well-defined and controllable lipid model system. Several methods exist to reconstitute membrane proteins in lipid systems but usually the reconstitution success is tested at the end of the experiment and often by an additional and indirect method...
November 8, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27812115/dynamic-cholesterol-conditioned-dimerization-of-the-g-protein-coupled-chemokine-receptor-type-4
#17
Kristyna Pluhackova, Stefan Gahbauer, Franziska Kranz, Tsjerk A Wassenaar, Rainer A Böckmann
G protein coupled receptors (GPCRs) allow for the transmission of signals across biological membranes. For a number of GPCRs, this signaling was shown to be coupled to prior dimerization of the receptor. The chemokine receptor type 4 (CXCR4) was reported before to form dimers and their functionality was shown to depend on membrane cholesterol. Here, we address the dimerization pattern of CXCR4 in pure phospholipid bilayers and in cholesterol-rich membranes. Using ensembles of molecular dynamics simulations, we show that CXCR4 dimerizes promiscuously in phospholipid membranes...
November 2016: PLoS Computational Biology
https://www.readbyqxmd.com/read/27726881/successful-strategies-to-determine-high-resolution-structures-of-gpcrs
#18
Jin Xiang, Eugene Chun, Chang Liu, Liang Jing, Zina Al-Sahouri, Lan Zhu, Wei Liu
G protein-coupled receptors (GPCRs) constitute the largest class of drug targets in the human genome, which highlights the importance of understanding the molecular basis of their activation, downstream signaling, and regulation. Since 2007, great progress has been made in the field of GPCR structure determination and their signaling complexes at the molecular level. Here, we summarize the high-resolution structures of over 30 different GPCRs with their co-crystallized ligands, and outline the successful strategies involved, including construct design, expression systems, and lipidic cubic phase (LCP) composition, and the many key technical parameters of the crystallization methods...
October 7, 2016: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/27687912/oxysterols-from-cholesterol-metabolites-to-key-mediators
#19
REVIEW
Valentin Mutemberezi, Owein Guillemot-Legris, Giulio G Muccioli
Oxysterols are cholesterol metabolites that can be produced through enzymatic or radical processes. They constitute a large family of lipids (i.e. the oxysterome) involved in a plethora of physiological processes. They can act through GPCR (e.g. EBI2, SMO, CXCR2), nuclear receptors (LXR, ROR, ERα) and through transporters or regulatory proteins. Their physiological effects encompass cholesterol, lipid and glucose homeostasis. Additionally, they were shown to be involved in other processes such as immune regulatory functions and brain homeostasis...
September 26, 2016: Progress in Lipid Research
https://www.readbyqxmd.com/read/27573285/regulatory-effects-of-grk2-on-gpcrs-and-non-gpcrs-and-possible-use-as-a-drug-target-review
#20
Chen-Chen Han, Yang Ma, Yifan Li, Yang Wang, Wei Wei
G protein-coupled receptor kinase 2 (GRK2) is a key member of the G protein-coupled receptor kinase (GRK) family. GRK2 activity is regulated by the C-terminus of GRK2 which contains a plekstrin homology domain and the N-terminus of GRK2 which contains the RGS homology domain with binding sites for several proteins and lipids such as G protein-coupled receptors (GPCRs), G protein, phospholipase C, phosphatidylinositol 4,5-bisphosphate, extracellular signal‑regulated kinase, protein kinase A and Gβγ...
October 2016: International Journal of Molecular Medicine
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