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Gpcr Structure

Dipak N Patil, Erumbi S Rangarajan, Scott J Novick, Bruce D Pascal, Douglas J Kojetin, Patrick R Griffin, Tina Izard, Kirill A Martemyanov
Signaling by the G protein Coupled Receptors (GPCRs) plays fundamental role in a vast number of essential physiological functions. Precise control of GPCR signaling requires action of Regulators of G protein Signaling (RGS) proteins that deactivate heterotrimeric G proteins. RGS proteins are elaborately regulated and comprise multiple domains and subunits, yet structural organization of these assemblies is poorly understood. Here we report a crystal structure and dynamics analyses of the multisubunit complex of RGS7, a major regulator of neuronal signaling with key roles in controlling a number of drug target GPCRs and links to neuropsychiatric disease, metabolism, and cancer...
December 12, 2018: ELife
David Goricanec, Franz Hagn
G-proteins are essential switch points at the cell membrane that control downstream signaling by their ability to adopt an inactive, GDP-bound or an active, GTP-bound state. Among other exchange factors, G-protein coupled receptors (GPCRs) induce exchange of GDP to GTP and thus promote the active state of the G-protein. The nucleotide-binding α subunit of the G-protein undergoes major conformational changes upon nucleotide binding. Thus, an NMR analysis of the two distinct nucleotide-bound states is essential for a more detailed understanding of associated structural changes...
December 11, 2018: Biomolecular NMR Assignments
Jie Yin, Karen Chapman, Lindsay D Clark, Zhenhua Shao, Dominika Borek, Qingping Xu, Junmei Wang, Daniel M Rosenbaum
The NK1 tachykinin G-protein-coupled receptor (GPCR) binds substance P, the first neuropeptide to be discovered in mammals. Through activation of NK1 R, substance P modulates a wide variety of physiological and disease processes including nociception, inflammation, and depression. Human NK1 R (hNK1 R) modulators have shown promise in clinical trials for migraine, depression, and emesis. However, the only currently approved drugs targeting hNK1 R are inhibitors for chemotherapy-induced nausea and vomiting (CINV)...
December 11, 2018: Proceedings of the National Academy of Sciences of the United States of America
Otavio Cabral-Marques, Alexandre Marques, Lasse Melvær Giil, Roberta De Vito, Judith Rademacher, Jeannine Günther, Tanja Lange, Jens Y Humrich, Sebastian Klapa, Susanne Schinke, Lena F Schimke, Gabriele Marschner, Silke Pitann, Sabine Adler, Ralf Dechend, Dominik N Müller, Ioana Braicu, Jalid Sehouli, Kai Schulze-Forster, Tobias Trippel, Carmen Scheibenbogen, Annetine Staff, Peter R Mertens, Madlen Löbel, Justin Mastroianni, Corinna Plattfaut, Frank Gieseler, Duska Dragun, Barbara Elizabeth Engelhardt, Maria J Fernandez-Cabezudo, Hans D Ochs, Basel K Al-Ramadi, Peter Lamprecht, Antje Mueller, Harald Heidecke, Gabriela Riemekasten
Autoantibodies have been associated with autoimmune diseases. However, studies have identified autoantibodies in healthy donors (HD) who do not develop autoimmune disorders. Here we provide evidence of a network of immunoglobulin G (IgG) autoantibodies targeting G protein-coupled receptors (GPCR) in HD compared to patients with systemic sclerosis, Alzheimer's disease, and ovarian cancer. Sex, age and pathological conditions affect autoantibody correlation and hierarchical clustering signatures, yet many of the correlations are shared across all groups, indicating alterations to homeostasis...
December 6, 2018: Nature Communications
Suchithranga M D C Perera, Udeep Chawla, Utsab Raj Shrestha, Debsindhu Bhowmik, Andrey V Struts, Shuo Qian, Xiang-Qiang Chu, Michael F Brown
Knowledge of the activation principles for G-protein-coupled receptors (GPCRs) is critical to development of new pharmaceuticals. Rhodopsin is the archetype for the largest GPCR family, yet the changes in protein dynamics that trigger signaling are not fully understood. Here we show that rhodopsin can be investigated by small-angle neutron scattering (SANS) in fully protiated detergent micelles under contrast matching to resolve the protein structure. In SANS studies of membrane proteins, the zwitterionic detergent [(Cholamidopropyl)dimethylammonio]-propanesulfonate (CHAPS) is advantageous because of the low contrast difference between the hydrophobic core and hydrophilic head groups as compared to alkyl glycoside detergents...
November 29, 2018: Journal of Physical Chemistry Letters
Longrong Wang, Yuan Yuan, Xin Chen, Jiangfan Chen, Yanzhi Guo, Menglong Li, Chuan Li, Xuemei Pu
Accumulated experimental evidence indicated that G-protein coupled receptors (GPCRs) could form biologically relevant oligomers and hetero-oligomers possess different functional properties from monomers and homo-oligomers, for example, unique pharmacology. However, the urgent lack of crystal structures of the GPCR oligomers results in very limited knowledge about their structural and functional mechanisms. In this work, we utilized a multiscale simulation strategy coupled with principal component analysis, correlation analysis and a protein structure network to study the hetero-dimerization of the μ-OR and δ-OR...
November 27, 2018: Physical Chemistry Chemical Physics: PCCP
Gemma Navarro, Mireia Medrano, David Aguinaga, Ignacio Vega-Quiroga, Alejandro Lillo, Jasmina Jiménez, Mireia Casanovas, Enric I Canela, Josefa Mallol, Katia Gysling, Rafael Franco
Stress is one of the factors underlying drug seeking behavior that often goes in parallel with loss of appetite. We here demonstrate that orexin 1 receptors (OX1 R) may form heteromeric complexes with the corticotropin releasing factor CRF2 receptor. Two specific features of the heteromer were a cross-antagonism and a blockade by CRF2 of OX1 R signaling. In cells expressing one of the receptors, agonist-mediated signal transduction mechanisms were potentiated by amphetamine. Sigma 1 (σ1 ) and 2 (σ2 ) receptors are targets of drugs of abuse and, despite sharing a similar name, the two receptors are structurally unrelated and their physiological role is not known...
November 19, 2018: Neuropharmacology
Eduardo Jardón-Valadez, Derik Castillo-Guajardo, Iván Martínez-Luis, Rubén Gutiérrez-Sagal, Teresa Zariñán, Alfredo Ulloa-Aguirre
Follicle-stimulating hormone receptor (FSHR) is a G-protein coupled receptor (GPCR) and a prototype of the glycoprotein hormone receptors subfamily of GPCRs. Structural data of the FSHR ectodomain in complex with follicle-stimulating hormone suggests a "pull and lift" activation mechanism that triggers a conformational change on the seven α-helix transmembrane domain (TMD). To analyze the conformational changes of the FSHR TMD resulting from sequence variants associated with reproductive impairment in humans, we set up a computational approach combining helix modeling and molecular simulation methods to generate conformational ensembles of the receptor at room (300 K) and physiological (310 K) temperatures...
2018: PloS One
Jonathan Elegheert, Ester Behiels, Benjamin Bishop, Suzanne Scott, Rachel E Woolley, Samuel C Griffiths, Eamon F X Byrne, Veronica T Chang, David I Stuart, E Yvonne Jones, Christian Siebold, A Radu Aricescu
Structural, biochemical and biophysical studies of eukaryotic soluble and membrane proteins require their production in milligram quantities. Although large-scale protein expression strategies based on transient or stable transfection of mammalian cells are well established, they are associated with high consumable costs, limited transfection efficiency or long and tedious selection of clonal cell lines. Lentiviral transduction is an efficient method for the delivery of transgenes to mammalian cells and unifies the ease of use and speed of transient transfection with the robust expression of stable cell lines...
December 2018: Nature Protocols
Janosch Ehrenmann, Jendrik Schöppe, Christoph Klenk, Mathieu Rappas, Lutz Kummer, Andrew S Doré, Andreas Plückthun
Parathyroid hormone 1 receptor (PTH1R) is a class B multidomain G-protein-coupled receptor (GPCR) that controls calcium homeostasis. Two endogenous peptide ligands, parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP), activate the receptor, and their analogs teriparatide and abaloparatide are used in the clinic to increase bone formation as an effective yet costly treatment for osteoporosis. Activation of PTH1R involves binding of the peptide ligand to the receptor extracellular domain (ECD) and transmembrane domain (TMD), a hallmark of class B GPCRs...
November 19, 2018: Nature Structural & Molecular Biology
Monica de Gaetano, Eibhlín Butler, Kevin Gahan, Andrea Zanetti, Mariam Marai, Jianmin Chen, Antonino Cacace, Emily Hams, Catherine Maingot, Alisha McLoughlin, Eoin Brennan, Xavier Leroy, Christine E Loscher, Padraic Fallon, Mauro Perretti, Catherine Godson, Patrick J Guiry
Lipoxins (LXs) are endogenously generated eicosanoids with potent bio-actions consistent with attenuation of inflammation. The costly synthesis and metabolic instability of LXs may limit their therapeutic potential. Here we report the synthesis and characterization of novel imidazole-/oxazole-containing synthetic-LX-mimetics (sLXms). The key steps of asymmetric synthesis of putative sLXms include a Suzuki reaction and an asymmetric ketone reduction. The effect of the novel compounds on inflammatory responses was assessed using a human monocyte cell line stably expressing a Nuclear Factor Kappa B (NFkB) reporter gene, by investigating downstream cytokine secretion...
October 23, 2018: European Journal of Medicinal Chemistry
K Tanuj Sapra, Patrizia M Spoerri, Andreas Engel, David Alsteens, Daniel J Müller
G protein-coupled receptors (GPCRs) relay extracellular information across cell membranes through a continuum of conformations that are not always captured in structures. Hence, complementary approaches are required to quantify the physical and chemical properties of the dynamic conformations linking to GPCR function. Atomic force microscopy (AFM)-based high-resolution imaging and force spectroscopy are unique methods to scrutinize GPCRs and to sense their interactions. Here, we exemplify recent AFM-based applications to directly observe the supramolecular assembly of GPCRs in native membranes, to measure the ligand-binding free-energy landscape, and how interactions modulate the structural properties of GPCRs...
November 6, 2018: Current Opinion in Cell Biology
Ichio Shimada, Takumi Ueda, Yutaka Kofuku, Matthew T Eddy, Kurt Wüthrich
The 826 G protein-coupled receptors (GPCRs) in the human proteome regulate key physiological processes and thus have long been attractive drug targets. With the crystal structures of more than 50 different human GPCRs determined over the past decade, an initial platform for structure-based rational design has been established for drugs that target GPCRs, which is currently being augmented with cryo-electron microscopy (cryo-EM) structures of higher-order GPCR complexes. Nuclear magnetic resonance (NMR) spectroscopy in solution is one of the key approaches for expanding this platform with dynamic features, which can be accessed at physiological temperature and with minimal modification of the wild-type GPCR covalent structures...
November 9, 2018: Nature Reviews. Drug Discovery
Ting Ban, Xun Li, Xiaochuan Ma, Hui Yang, Yunpeng Song, Yaping Sun, Michelle Shen, Na Li, Mei-Yun Zhang, Yingli Ma, Wenge Zhong, Mingqiang Zhang, Liaoyuan A Hu
Biased ligands of G protein-coupled receptors (GPCR) may have improved therapeutic benefits and safety profiles. However, the molecular mechanism of GPCR biased signaling remains largely unknown. Using apelin receptor (APJ) as a model, we systematically investigated the potential effects of amino acid residues around the orthosteric binding site on biased signaling. We discovered that a single residue mutation I109A (I1093.32 ) in the transmembrane domain 3 (TM3) located in the deep ligand binding pocket was sufficient to convert a balanced APJ into a G protein signaling biased receptor...
November 8, 2018: Biochemical Journal
Alexander Marciniak, Sara M Camp, Joe G N Garcia, Robin Polt
Sphingolipids represent an essential class of lipids found in all eukaryotes, and strongly influence cellular signal transduction. Autoimmune diseases like asthma and multiple sclerosis (MS) are mediated by the sphingosine-1-phosphate receptor 1 (S1P1 ) to express a variety of symptoms and disease patterns. Inspired by its natural substrate, an array of artificial sphingolipid derivatives has been developed to target this specific G protein-coupled receptor (GPCR) in an attempt to suppress autoimmune disorders...
October 26, 2018: Bioorganic & Medicinal Chemistry Letters
Raphael Silvanus Haider, Amod Godbole, Carsten Hoffmann
Advances in resolving crystal structures of GPCRs and their binding partners as well as improvements in live-cell microscopy and the fluorescent proteins pallet has greatly driven new ideas for designing optical sensors for the same. Sensors have been developed to monitor ligand binding as well as the ensuing ligand-induced conformational changes in GPCRs, G-proteins and arrestins. In this review we will highlight the functionality of such sensor designs starting from monitoring ligand binding to receptor activation and interaction with arrestins...
November 5, 2018: Current Opinion in Cell Biology
Takero Miyagawa, Hiroyasu Koteishi, Yoichiro Kamimura, Yukihiro Miyanaga, Kohei Takeshita, Atsushi Nakagawa, Masahiro Ueda
G protein interacting protein 1 (Gip1) binds and sequesters heterotrimeric G proteins in the cytosolic pool, thus regulating G protein-coupled receptor (GPCR) signalling for eukaryotic chemotaxis. Here, we report the underlying structural basis of Gip1 function. The crystal structure reveals that the region of Gip1 that binds to the G protein has a cylinder-like fold with a central hydrophobic cavity composed of six α-helices. Mutagenesis and biochemical analyses indicate that the hydrophobic cavity and the hydrogen bond network at the entrance of the cavity are essential for complex formation with the geranylgeranyl modification on the Gγ subunit...
November 6, 2018: Nature Communications
Julie Schwartz, Marie-Pierre Dubos, Jérémy Pasquier, Céline Zatylny-Gaudin, Pascal Favrel
Chordate gastrin/cholecystokinin (G/CCK) and ecdysozoan sulfakinin (SK) signalling systems represent divergent evolutionary scenarios of a common ancestral signalling system. The present article investigates for the first time the evolution of the CCK/SK signalling system in a member of the Lophotrochozoa, the second clade of protostome animals. We identified two G protein-coupled receptors (GPCR) in the oyster Crassostrea gigas (Mollusca), phylogenetically related to chordate CCK receptors (CCKR) and to ecdysozoan sulfakinin receptors (SKR)...
November 6, 2018: Scientific Reports
Paige N Castleman, Chandler K Sears, Judith A Cole, Daniel L Baker, Abby L Parrill
G protein-coupled receptors (GPCR) are integral membrane proteins of considerable interest as targets for drug development. GPCR ligand interaction studies often have a starting point with either crystal structures or comparative models. The majority of GPCR do not have experimentally-characterized 3-dimensional structures, so comparative modeling, also called homology modeling, is a good structure-based starting point. Comparative modeling is a widely used method for generating models of proteins with unknown structures by analogy to crystallized proteins that are expected to exhibit structural conservation...
January 2019: Journal of Molecular Graphics & Modelling
Marcin Maziarz, Anthony Leyme, Arthur Marivin, Alex Luebbers, Prachi P Patel, Zhe Chen, Stephen R Sprang, Mikel Garcia-Marcos
The causative role of G protein-couple receptor (GPCR) pathway mutations in uveal melanoma has been well established. Nearly all UMs bear an activating mutation in a GPCR pathway mediated by G proteins of the Gq/11 family, driving tumor initiation and possibly metastatic progression. Thus, targeting this pathway holds therapeutic promise for managing UM. However, direct targeting of oncogenic Gαq/11 mutants, present in ~90% of UMs, is complicated by the belief that these mutants structurally resemble active Gαq/11 wild-type...
October 23, 2018: Journal of Biological Chemistry
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