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https://www.readbyqxmd.com/read/28609478/purification-of-family-b-g-protein-coupled-receptors-using-nanodiscs-application-to-human-glucagon-like-peptide-1-receptor
#1
Yingying Cai, Yuting Liu, Kelly J Culhane, Brian T DeVree, Yang Yang, Roger K Sunahara, Elsa C Y Yan
Family B G protein-coupled receptors (GPCRs) play vital roles in hormone-regulated homeostasis. They are drug targets for metabolic diseases, including type 2 diabetes and osteoporosis. Despite their importance, the signaling mechanisms for family B GPCRs at the molecular level remain largely unexplored due to the challenges in purification of functional receptors in sufficient amount for biophysical characterization. Here, we purified the family B GPCR human glucagon-like peptide-1 (GLP-1) receptor (GLP1R), whose agonists, e...
2017: PloS One
https://www.readbyqxmd.com/read/28571491/insights-into-unbound-bound-states-of-gpr142-receptor-in-a-membrane-aqueous-system-using-molecular-dynamics-simulations
#2
Aman Chandra Kaushik, Shakti Sahi
G protein coupled receptors (GPCRs) are source machinery in signal transduction pathways and being one of the major therapeutic targets play a significant in drug discovery. GPR142, an orphan GPCR, has been implicated in the regulation of insulin, thereby having a crucial role in Type II diabetes management. Deciphering of the structures of orphan GPCRs (O-GPCRs) offer better prospects for advancements in research in ion translocation and transduction of extracellular signals. As the crystallographic structure of GPR142 is not available in PDB, therefore, threading and abinitio based approaches were used for 3D modeling of GPR142...
June 1, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28547763/new-approaches-towards-the-understanding-of-integral-membrane-proteins-a-structural-perspective-on-g-protein-coupled-receptors
#3
REVIEW
Reinhard Grisshammer
Three-dimensional structure determination of integral membrane proteins has advanced in unprecedented detail our understanding of mechanistic events of how ion channels, transporters, receptors, and enzymes function. This exciting progress required a tremendous amount of methods development, as exemplified here with G protein-coupled receptors (GPCRs): Optimizing the production of GPCRs in recombinant hosts; increasing the probability of crystal formation using high-affinity ligands, nanobodies, and minimal G proteins for co-crystallization, thus stabilizing receptors into one conformation; using the T4 lysozyme technology and other fusion partners to promote crystal contacts; advancing crystallization methods including the development of novel detergents, and miniaturization and automation of the lipidic cubic phase crystallization method; the concept of conformational thermostabilization of GPCRs; and developing microfocus X-ray synchrotron technologies to analyze small GPCR crystals...
May 25, 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/28508109/solvent-accessibility-of-discrete-residue-positions-in-the-polypeptide-hormone-glucagon-by-19-f-nmr-observation-of-4-fluorophenylalanine
#4
Yaguang Hou, Wanhui Hu, Xiaona Li, John J Skinner, Dongsheng Liu, Kurt Wüthrich
The amino acid 4-fluoro-L-phenylalanine (4F-Phe) was introduced at the positions of Phe6 and Phe22 in the 29-residue polypeptide hormone glucagon by expressing glucagon in E. coli in the presence of an excess of 4F-Phe. Glucagon regulates blood glucose homeostasis by interaction with the glucagon receptor (GCGR), a class B GPCR. By referencing to the 4F-Phe chemical shifts at varying D2O concentrations, the solvent exposure of the two Phe sites along the glucagon sequence was determined, showing that 4F-Phe6 was fully solvent exposed and 4F-Phe22 was only partially exposed...
May 15, 2017: Journal of Biomolecular NMR
https://www.readbyqxmd.com/read/28473666/the-palmitoylation-of-the-n-terminal-extracellular-cys37-mediates-the-nuclear-translocation-of-vpac1-contributing-to-its-anti-apoptotic-activity
#5
Rongjie Yu, Hongyu Liu, Xinhe Peng, Yue Cui, Suqin Song, Like Wang, Huahua Zhang, An Hong, Tianhong Zhou
VPAC1 is class B G protein-coupled receptors (GPCR) shared by pituitary adenylate cyclase activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP). The first cysteine (Cys37) in the N-terminal extracellular domain of mature VPAC1 is a free Cys not involved in the formation of conserved intramolecular disulfide bonds. In order to investigate the biological role of this Cys37 in VPAC1, the wild-type VPAC1 and Cys37/Ala mutant (VPAC1-C37/A) were expressed stably as fusion proteins with enhanced yellow fluorescent protein (EYFP) respectively in Chinese hamster ovary (CHO) cells...
April 27, 2017: Oncotarget
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/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
#7
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/28374590/binding-site-characterization-of-am1336-a-novel-covalent-inverse-agonist-at-human-cannabinoid-2-receptor-using-mass-spectrometric-analysis
#8
Srikrishnan Mallipeddi, Simion Kreimer, Nikolai Zvonok, Kiran Vemuri, Barry L Karger, Alexander R Ivanov, Alexandros Makriyannis
Cannabinoid 2 receptor (CB2R), a Class-A G-protein coupled receptor (GPCR), is a promising drug target under a wide array of pathological conditions. Rational drug design has been hindered due to our poor understanding of the structural features involved in ligand binding. Binding of a high-affinity biarylpyrazole inverse agonist AM1336 to a library of the human CB2 receptor (hCB2R) cysteine-substituted mutants provided indirect evidence that two cysteines in transmembrane helix-7 (H7) were critical for the covalent attachment...
June 19, 2017: Journal of Proteome Research
https://www.readbyqxmd.com/read/28373559/conformational-equilibria-of-light-activated-rhodopsin-in-nanodiscs
#9
Ned Van Eps, Lydia N Caro, Takefumi Morizumi, Ana Karin Kusnetzow, Michal Szczepek, Klaus Peter Hofmann, Timothy H Bayburt, Stephen G Sligar, Oliver P Ernst, Wayne L Hubbell
Conformational equilibria of G-protein-coupled receptors (GPCRs) are intimately involved in intracellular signaling. Here conformational substates of the GPCR rhodopsin are investigated in micelles of dodecyl maltoside (DDM) and in phospholipid nanodiscs by monitoring the spatial positions of transmembrane helices 6 and 7 at the cytoplasmic surface using site-directed spin labeling and double electron-electron resonance spectroscopy. The photoactivated receptor in DDM is dominated by one conformation with weak pH dependence...
April 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28370663/activation-mechanisms-of-the-first-sphingosine-1-phosphate-receptor
#10
Alisha D Caliman, Yinglong Miao, J Andrew McCammon
Activation of the first sphingosine-1-phosphate receptor (S1PR1 ) promotes permeability of the blood brain barrier, astrocyte and neuronal protection, and lymphocyte egress from secondary lymphoid tissues. Although an agonist often activates the S1PR1 , the receptor exhibits high levels of basal activity. In this study, we performed long-timescale molecular dynamics and accelerated molecular dynamics (aMD) simulations to investigate activation mechanisms of the ligand-free (apo) S1PR1 . In the aMD enhanced sampling simulations, we observed four independent events of activation, which is characterized by close interaction between Y311(7...
June 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/28325781/20-hete-signals-through-g-protein-coupled-receptor-gpr75-gq-to-affect-vascular-function-and-trigger-hypertension
#11
Victor Garcia, Ankit Gilani, Brian Shkolnik, Varunkumar Pandey, Frank Fan Zhang, Rambabu Dakarapu, Shyam K Gandham, N Rami Reddy, Joan P Graves, Artiom Gruzdev, Darryl C Zeldin, Jorge H Capdevila, John R Falck, Michal Laniado Schwartzman
RATIONALE: 20-Hydroxyeicosatetraenoic acid (20-HETE), one of the principle cytochrome P450 eicosanoids, is a potent vasoactive lipid whose vascular effects include stimulation of smooth muscle contractility, migration, and proliferation, as well as endothelial cell dysfunction and inflammation. Increased levels of 20-HETE in experimental animals and in humans are associated with hypertension, stroke, myocardial infarction, and vascular diseases. OBJECTIVE: To date, a receptor/binding site for 20-HETE has been implicated based on the use of specific agonists and antagonists...
May 26, 2017: Circulation Research
https://www.readbyqxmd.com/read/28290516/antagonizing-effects-of-membrane-acting-androgens-on-the-eicosanoid-receptor-oxer1-in-prostate-cancer
#12
Konstantina Kalyvianaki, Veronika Gebhart, Nikolaos Peroulis, Christina Panagiotopoulou, Fotini Kiagiadaki, Iosif Pediaditakis, Michalis Aivaliotis, Eleni Moustou, Maria Tzardi, George Notas, Elias Castanas, Marilena Kampa
Accumulating evidence during the last decades revealed that androgen can exert membrane initiated actions that involve signaling via specific kinases and the modulation of significant cellular processes, important for prostate cancer cell growth and metastasis. Results of the present work clearly show that androgens can specifically act at the membrane level via the GPCR oxoeicosanoid receptor 1 (OXER1) in prostate cancer cells. In fact, OXER1 expression parallels that of membrane androgen binding in prostate cancer cell lines and tumor specimens, while in silico docking simulation of OXER1 showed that testosterone could bind to OXER1 within the same grove as 5-OxoETE, the natural ligand of OXER1...
March 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28261474/expression-of-fatty-acid-sensing-g-protein-coupled-receptors-in-peripartal-holstein-cows
#13
Alea Agrawal, Abdulrahman Alharthi, Mario Vailati-Riboni, Zheng Zhou, Juan J Loor
BACKGROUND: G-protein coupled receptors (GPCR), also referred as Free Fatty Acid Receptors (FFAR), are widely studied within human medicine as drug targets for metabolic disorders. To combat metabolic disorders prevalent in dairy cows during the transition period, which co-occur with negative energy balance and changes to lipid and glucose metabolism, it may be helpful to identify locations and roles of FFAR and other members of the GPCR family in bovine tissues. RESULTS: Quantitative RT-PCR (qPCR) of subcutaneous adipose, liver, and PMNL samples during the transition period (-10, +7, and +20 or +30 d) were used for expression profiling of medium- (MCFA) and long-chain fatty acid (LCFA) receptors GPR120 and GPR40, MCFA receptor GPR84, and niacin receptor HCAR2/3...
2017: Journal of Animal Science and Biotechnology
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
#14
Mark E Schnute, Matthew D McReynolds, Jeffrey Carroll, Jill 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 G protein-coupled receptor 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 2 orders of magnitude improved potency...
March 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
#15
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
#16
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...
April 1, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28159877/g-protein-coupled-receptor-signaling-in-cilia
#17
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
#18
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 23, 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
#19
REVIEW
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
#20
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...
January 10, 2017: Biochemistry
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