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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
#1
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
#2
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
#3
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
#4
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/28516903/molecular-mechanism-of-g%C3%AE-i-activation-by-non-gpcr-proteins-with-a-g%C3%AE-binding-and-activating-motif
#5
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/28513578/crystal-structure-of-a-multi-domain-human-smoothened-receptor-in-complex-with-a-super-stabilizing-ligand
#6
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
https://www.readbyqxmd.com/read/28512295/camp-dependent-cell-differentiation-triggered-by-activated-crhr1-in-hippocampal-neuronal-cells
#7
Carolina Inda, Juan José Bonfiglio, Paula A Dos Santos Claro, Sergio A Senin, Natalia G Armando, Jan M Deussing, Susana Silberstein
Corticotropin-releasing hormone receptor 1 (CRHR1) activates the atypical soluble adenylyl cyclase (sAC) in addition to transmembrane adenylyl cyclases (tmACs). Both cAMP sources were shown to be required for the phosphorylation of ERK1/2 triggered by activated G protein coupled receptor (GPCR) CRHR1 in neuronal and neuroendocrine contexts. Here, we show that activated CRHR1 promotes growth arrest and neurite elongation in neuronal hippocampal cells (HT22-CRHR1 cells). By characterising CRHR1 signalling mechanisms involved in the neuritogenic effect, we demonstrate that neurite outgrowth in HT22-CRHR1 cells takes place by a sAC-dependent, ERK1/2-independent signalling cascade...
May 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28511989/biased-agonism-antagonism-at-the-angii-at1-receptor-implications-for-adrenal-aldosterone-production-and-cardiovascular-therapy
#8
REVIEW
Jennifer Maning, Shmuel Negussie, Michelle A Clark, Anastasios Lymperopoulos
Many of the effects of angiotensin II (AngII), including adrenocortical aldosterone release, are mediated by the AngII type 1 receptor (AT1R), a receptor with essential roles in cardiovascular homeostasis. AT1R belongs to the G protein-coupled receptor (GPCR) superfamily, mainly coupling to the Gq/11 type of G proteins. However, it also signals through βarrestins, oftentimes in parallel to eliciting G protein-dependent signaling. This has spurred infinite possibilities for cardiovascular pharmacology, since various beneficial effects are purportedly exerted by AT1R via βarrestins, unlike AT1R-induced G protein-mediated pathways that usually result in damaging cardiovascular effects, including hypertension and aldosterone elevation...
May 13, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological 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
#9
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/28508075/fast-iodide-sad-phasing-for-high-throughput-membrane-protein-structure-determination
#10
Igor Melnikov, Vitaly Polovinkin, Kirill Kovalev, Ivan Gushchin, Mikhail Shevtsov, Vitaly Shevchenko, Alexey Mishin, Alexey Alekseev, Francisco Rodriguez-Valera, Valentin Borshchevskiy, Vadim Cherezov, Gordon A Leonard, Valentin Gordeliy, Alexander Popov
We describe a fast, easy, and potentially universal method for the de novo solution of the crystal structures of membrane proteins via iodide-single-wavelength anomalous diffraction (I-SAD). The potential universality of the method is based on a common feature of membrane proteins-the availability at the hydrophobic-hydrophilic interface of positively charged amino acid residues with which iodide strongly interacts. We demonstrate the solution using I-SAD of four crystal structures representing different classes of membrane proteins, including a human G protein-coupled receptor (GPCR), and we show that I-SAD can be applied using data collection strategies based on either standard or serial x-ray crystallography techniques...
May 2017: Science Advances
https://www.readbyqxmd.com/read/28507272/phosphatidylinositol-5-phosphate-4-kinase-regulates-early-endosomal-dynamics-during-clathrin-mediated-endocytosis
#11
Kumari Kamalesh, Deepti Trivedi, Sarah Toscano, Sanjeev Sharma, Sourav Kolay, Padinjat Raghu
Endocytic turnover is essential to regulate the protein composition and function of the plasma membrane thus regulating the plasma membrane levels of many receptors. In Drosophila photoreceptors, photon absorption by the GPCR rhodopsin 1 (Rh1) triggers its endocytosis by clathrin-mediated endocytosis (CME). We find that CME of Rh1 is regulated by phosphatidylinositol 5 phosphate 4-kinase (PIP4K). Flies lacking PIP4K show mislocalization of Rh1 on expanded endomembranes within the cell body. This mislocalization of Rh1 was dependent on the formation of an expanded Rab5 compartment...
May 15, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28505258/modelling-and-mathematical-analysis-of-the-m-_-2-receptor-dependent-joint-signalling-and-secondary-messenger-network-in-cho-cells
#12
Benjamin Engelhardt, Janine Holze, Christina Elliott, George S Baillie, Maik Kschischo, Holger Fröhlich
The muscarinic M$_{2}$ receptor is a prominent member of the GPCR family and strongly involved in heart diseases. Recently published experimental work explored the cellular response to iperoxo-induced M$_{2}$ receptor stimulation in Chinese hamster ovary (CHO) cells. To better understand these responses, we modelled and analysed the muscarinic M$_{2}$ receptor-dependent signalling pathway combined with relevant secondary messenger molecules using mass action. In our literature-based joint signalling and secondary messenger model, all binding and phosphorylation events are explicitly taken into account in order to enable subsequent stoichiometric matrix analysis...
May 15, 2017: Mathematical Medicine and Biology: a Journal of the IMA
https://www.readbyqxmd.com/read/28502923/g-protein-coupled-receptor-signaling-through-gpr176-gz-and-rgs16-tunes-time-in-the-center-of-the-circadian-clock-review
#13
Kaoru Goto, Masao Doi, Tianyu Wang, Sumihiro Kunisue, Iori Murai, Hitoshi Okamura
G-protein-coupled receptors (GPCRs) constitute an immensely important class of drug targets with diverse clinical applications. There are still more than 120 orphan GPCRs whose cognate ligands and physiological functions are not known. A set of circadian pacemaker neurons that governs daily rhythms in behavior and physiology resides in the suprachiasmatic nucleus (SCN) in the brain. Malfunction of the circadian clock has been linked to a multitude of diseases, such as sleeping disorders, obesity, diabetes, cardiovascular diseases, and cancer, which makes the clock an attractive target for drug development...
May 13, 2017: Endocrine Journal
https://www.readbyqxmd.com/read/28502792/drug-binding-poses-relate-structure-with-efficacy-in-the-%C3%AE-opioid-receptor
#14
Katy J Sutcliffe, Graeme Henderson, Eamonn Kelly, Richard B Sessions
The μ-opioid receptor (MOPr) is a clinically important G protein-coupled receptor (GPCR) which couples to Gi/o proteins and arrestins. At present the receptor conformational changes that occur following agonist binding and activation are poorly understood. This study has employed molecular dynamics simulations to investigate the binding mode and receptor conformational changes induced by structurally similar opioid ligands of widely differing intrinsic agonist efficacy, norbuprenorphine, buprenorphine and diprenorphine...
May 11, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28499989/melanocortin-receptor-accessory-proteins-mraps-functions-in-the-melanocortin-system-and-beyond
#15
REVIEW
Alix A J Rouault, Dinesh K Srinivasan, Terry C Yin, Abigail A Lee, Julien A Sebag
G-protein coupled receptors (GPCRs) are regulated by numerous proteins including kinases, G-proteins, β-arrestins and accessory proteins. Several families of GPCR accessory proteins like Receptor Activity Modifying Proteins, Receptor Transporting Proteins and Melanocortin Receptor Accessory Proteins (MRAPs) have been identified as regulator of receptor trafficking, signaling and ligand specificity. The MRAP family contains two members, MRAP1 and MRAP2, responsible for the formation of a functional ACTH receptor and for the regulation of energy homeostasis respectively...
May 9, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28499341/positive-detection-of-gpcr-antagonists-using-a-system-for-inverted-expression-of-a-fluorescent-reporter-gene
#16
Nobuo Fukuda, Misato Kaishima, Jun Ishii, Shinya Honda
The yeast Saccharomyces cerevisiae is a useful eukaryotic host organism for studying GPCRs as monomolecular models. Fluorescent reporter gene assays for GPCRs provide a convenient assay for measuring receptor activity using fluorometric instruments. Generally, these assays detect receptor activation by agonistic ligands as the induction of fluorescent reporter expression, whereas antagonistic activities are detected by competition with agonistic ligands, resulting in decreases in fluorescence intensity. In the current study, we established a system for inverted expression of a fluorescent reporter by incorporating a PEST-tag and finding out a promoter inhibited by activation of the GPCR signaling pathway from yeast endogenous promoters...
May 12, 2017: ACS Synthetic Biology
https://www.readbyqxmd.com/read/28495999/%C3%AE-arrestin-mediated-regulation-of-the-human-ether-a-go-go-related-gene-herg-potassium-channel
#17
Matthew G Sangoi, Shawn M Lamothe, Jun Guo, Tonghua Yang, Wentao Li, Ellen G Avery, John T Fisher, Shetuan Zhang
The rapidly activating delayed rectifier K(+) channel (IKr) is encoded by the human ether-a-go-go-related gene (hERG), which is important for the repolarization of the cardiac action potential. Mutations in hERG or drugs can impair the function or decrease the expression level of hERG channels, leading to long QT syndrome (LQTS). Thus, it is important to understand hERG channel trafficking and its regulation. For this purpose, G protein-coupled receptors (GPCRs), which regulate a vast array of cellular processes, represent a useful route...
May 11, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28495495/translating-in-vitro-ligand-bias-into-in-vivo-efficacy
#18
REVIEW
Louis M Luttrell, Stuart Maudsley, Diane Gesty-Palmer
It is increasingly apparent that ligand structure influences both the efficiency with which G protein-coupled receptors (GPCRs) engage their downstream effectors and the manner in which they are activated. Thus, 'biased' agonists, synthetic ligands whose intrinsic efficacy differs from the native ligand, afford a strategy for manipulating GPCR signaling in ways that promote beneficial signals while blocking potentially deleterious ones. Still, there are significant challenges in relating in vitro ligand efficacy, which is typically measured in heterologous expression systems, to the biological response in vivo, where the ligand is acting on natively expressed receptors and in the presence of the endogenous ligand...
May 7, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28493967/water-permeation-through-the-internal-water-pathway-in-activated-gpcr-rhodopsin
#19
Katsufumi Tomobe, Eiji Yamamoto, Kholmirzo Kholmurodov, Kenji Yasuoka
Rhodopsin is a light-driven G-protein-coupled receptor that mediates signal transduction in eyes. Internal water molecules mediate activation of the receptor in a rhodopsin cascade reaction and contribute to conformational stability of the receptor. However, it remains unclear how internal water molecules exchange between the bulk and protein inside, in particular through a putative solvent pore on the cytoplasmic. Using all-atom molecular dynamics simulations, we identified the solvent pore on cytoplasmic side in both the Meta II state and the Opsin...
2017: PloS One
https://www.readbyqxmd.com/read/28489817/selectivity-determinants-of-gpcr-g-protein-binding
#20
Tilman Flock, Alexander S Hauser, Nadia Lund, David E Gloriam, Santhanam Balaji, M Madan Babu
The selective coupling of G-protein-coupled receptors (GPCRs) to specific G proteins is critical to trigger the appropriate physiological response. However, the determinants of selective binding have remained elusive. Here we reveal the existence of a selectivity barcode (that is, patterns of amino acids) on each of the 16 human G proteins that is recognized by distinct regions on the approximately 800 human receptors. Although universally conserved positions in the barcode allow the receptors to bind and activate G proteins in a similar manner, different receptors recognize the unique positions of the G-protein barcode through distinct residues, like multiple keys (receptors) opening the same lock (G protein) using non-identical cuts...
May 10, 2017: Nature
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