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Gpcr Structure

Thomas Tarenzi, Vania Calandrini, Raffaello Potestio, Paolo Carloni
G-protein-coupled receptors (GPCRs) constitute as much as 30% of the overall proteins targeted by FDA-approved drugs. However, paucity of structural experimental information and low sequence identity between members of the family impair the reliability of traditional docking approaches and atomistic molecular dynamics simulations for in silico pharmacological applications. We present here a dual-resolution approach tailored for such low-resolution models. It couples a hybrid Molecular Mechanics/Coarse-Grained (MM/CG) scheme, previously developed by us for GPCR/ligand complexes, with a Hamiltonian-based Adaptive Resolution Scheme (H-AdResS) for the solvent...
February 14, 2019: Journal of Chemical Theory and Computation
Shu Li, Bohua Wu, Wei Han
Helical hinges are common in transmembrane (TM) proteins. Hinging motions of TM helices are associated with the functional dynamics of many important membrane proteins such as various G-protein coupled receptors (GPCR) and potassium channels. Although coarse-grained (CG) simulations are useful for studying membrane proteins, they are limited in describing accurately the hinge-related protein dynamics. In this study, we have overcome this limitation through a further development of the MARTINI CG model. The key improvement lay in implementation of additional local structural types and parameterization of the model against a structural library of TM helices obtained from the Protein Data Bank...
February 14, 2019: Journal of Physical Chemistry. B
Ernesto Gonzalez de Valdivia, Caroline Sandén, Robin Kahn, Björn Olde, Fredrik L M Leeb-Lundberg
GPR30, or G protein-coupled estrogen receptor (GPER), is a G protein-coupled receptor (GPCR) that is currently attracting considerable attention in breast cancer and cardiometabolic regulation. The receptor was reported to be a novel membrane estrogen receptor mediating rapid non-genomic responses. However, questions remain about both the cognate ligand and the subcellular localization of receptor activity. Here, we used HEK293 cells ectopically expressing N-terminally FLAG-tagged human GPR30 and three unique antibodies (Ab) specifically targeting the receptor N-terminal domain (N-domain) to investigate the role of N -glycosylation in receptor maturation and activity, the latter assayed by constitutive receptor-stimulated ERK1/2 activity...
February 13, 2019: Bioscience Reports
Neil J Grimsey, Ying Lin, Rachan Narala, Cara C Rada, Hilda Mejia-Pena, JoAnn Trejo
Endothelial dysfunction is induced by inflammatory mediators including multiple G protein-coupled receptor (GPCR) agonists.  However, the GPCR signaling pathways that promote endothelial dysfunction are incompletely understood. We previously showed that thrombin promotes endothelial barrier disruption through autophosphorylation and activation of p38 mitogen-activated protein kinase (MAPK) via a non-canonical TGF-b-activated protein kinase-1-binding protein-1 (TAB1)-and TAB2-dependent pathway rather than the canonical three-tiered kinase cascade...
February 13, 2019: Journal of Biological Chemistry
Jihye Park, Balaji Selvam, Keisuke Sanematsu, Noriatsu Shigemura, Diwakar Shukla, Erik Procko
Class C G protein-coupled receptors (GPCRs) are obligatory dimers that are particularly important for neuronal responses to endogenous and environmental stimuli. Ligand recognition through large extracellular domains leads to the reorganization of transmembrane regions to activate G protein signaling. While structures of individual domains are known, the complete architecture of a class C GPCR and the mechanism of interdomain coupling during receptor activation are unclear. By screening a mutagenesis library of the human class C sweet taste receptor subunit T1R2, we enhanced surface expression and identified a dibasic intracellular retention motif that modulates surface expression and co-trafficking with its heterodimeric partner T1R3...
February 5, 2019: Journal of Biological Chemistry
Wen-Dan Lu, Li Li, Yan-Jia Shen, Rui Zhou, Ran Yang, Xiao-Cong Pang, Guan-Hua Du
In this study, bioinformatics methods such as molecular docking and network pharmacology were adopted to establish Xiaoxuming Decoction (XXMD) "compound-vasodilatory and vasoconstrictory related G protein-coupled receptors (GPCR) targets" network, then the vascular function regulatory effective components and the potential targets of XXMD were analyzed. Based on the XXMD herb sources, the chemical structures of the compounds were retrieved from the national scientific data sharing platform for population and health pharmaceutical information center, TCMSP database and the latest research literatures...
December 2018: Zhongguo Zhong Yao za Zhi, Zhongguo Zhongyao Zazhi, China Journal of Chinese Materia Medica
Vsevolod V Gurevich, Eugenia V Gurevich
Arrestins play a key role in homologous desensitization of G protein-coupled receptors (GPCRs) and regulate several other vital signaling pathways in cells. Considering the critical roles of these proteins in cellular signaling, surprisingly few disease-causing mutations in human arrestins were described. Most of these are loss-of-function mutations of visual arrestin-1 that cause excessive rhodopsin signaling and hence night blindness. Only one dominant arrestin-1 mutation was discovered so far. It reduces the thermal stability of the protein, which likely results in photoreceptor death via unfolded protein response...
2019: Progress in Molecular Biology and Translational Science
Vsevolod V Gurevich, Eugenia V Gurevich
G protein-coupled receptors (GPCRs) are the largest family of signaling proteins targeted by more clinically used drugs than any other protein family. GPCR signaling via G proteins is quenched (desensitized) by the phosphorylation of the active receptor by specific GPCR kinases (GRKs) followed by tight binding of arrestins to active phosphorylated receptors. Thus, arrestins engage two types of receptor elements: those that contain GRK-added phosphates and those that change conformation upon activation. GRKs attach phosphates to serines and threonines in the GPCR C-terminus or any one the cytoplasmic loops...
January 28, 2019: Molecular and Cellular Endocrinology
Timo W M De Groof, Vladimir Bobkov, Raimond Heukers, Martine J Smit
The family of G protein-coupled receptors (GPCRs) is the largest class of membrane proteins and an important drug target due to their role in many (patho)physiological processes. Besides small molecules, GPCRs can be targeted by biologicals including antibodies and antibody fragments. This review describes the use of antibodies and in particular antibody fragments from camelid-derived heavy chain-only antibodies (nanobodies/VHHs/sdAbs) for detecting, stabilizing, modulating and therapeutically targeting GPCRs...
January 26, 2019: Molecular and Cellular Endocrinology
Marina Casiraghi, Elodie Point, Alexandre Pozza, Karine Moncoq, Jean-Louis Banères, Laurent J Catoire
Understanding the signal transduction mechanism mediated by the G Protein-Coupled Receptors (GPCRs) in eukaryote cells represents one of the main issues in modern biology. At the molecular level, various biophysical approaches have provided important insights on the functional plasticity of these complex allosteric machines. In this context, X-ray crystal structures published during the last decade represent a major breakthrough in GPCR structural biology, delivering important information on the activation process of these receptors through the description of the three-dimensional organization of their active and inactive states...
January 25, 2019: Molecular and Cellular Endocrinology
Fuhui Zhang, Yuan Yuan, Minghui Xiang, Yan-Zhi Guo, Meng-Long Li, Yijing Liu, Xue-Mei Pu
In this work, we combined accelerated molecular dynamics (aMD) and conventional molecular dynamics (cMD) simulations coupled with the potential of mean force (PMF), correlation analysis, principal component analysis (PCA) and protein structure network (PSN) to study the effects of dimerization and the mutations of I52V and V150A on the CCR5 homodimer, in order to elucidate the mechanism regarding cooperativity of the ligand binding between two protomers and to address the controversy about the mutation-induced dimer-separation...
January 28, 2019: Journal of Chemical Information and Modeling
Natarin Caengprasath, Aylin C Hanyaloglu
The pivotal and diverse roles G protein-coupled receptors (GPCRs) play in physiology are matched by the increasingly complex signal systems they activate. Over the past decade, our models of GPCR signaling systems also include a vital role of location in controlling GPCR signaling, whereby plasma membrane, clathrin-associated structures and a diverse endomembrane network provide highly specialized signal platforms for this superfamily of receptors. The aim of this review is to highlight the recent developments in this fast-evolving field, with particular emphasis on endocrine-relevant GPCRs...
January 22, 2019: Current Opinion in Cell Biology
Jan-Patrick Fischer, Ria Schönauer, Sylvia Els-Heindl, Donald Bierer, Johannes Koebberling, Bernd Riedl, Annette G Beck-Sickinger
Adrenomedullin (ADM) is a vasoactive peptide hormone of 52 amino acids and belongs to the calcitonin peptide superfamily. Its vasodilative effects are mediated by the interaction with the calcitonin receptor-like receptor (CLR), a class B G protein-coupled receptor (GPCR), associated with the receptor activity modifying protein 2 (RAMP2) and functionally described as AM-1 receptor (AM1 R). A disulfide-bonded ring structure consisting of six amino acids between Cys16 and Cys21 has been shown to be a key motif for receptor activation...
January 24, 2019: Journal of Peptide Science: An Official Publication of the European Peptide Society
Christian Munk, Eshita Mutt, Vignir Isberg, Louise F Nikolajsen, Janne M Bibbe, Tilman Flock, Michael A Hanson, Raymond C Stevens, Xavier Deupi, David E Gloriam
G-protein-coupled receptors (GPCRs) transduce physiological and sensory stimuli into appropriate cellular responses and mediate the actions of one-third of drugs. GPCR structural studies have revealed the general bases of receptor activation, signaling, drug action and allosteric modulation, but so far cover only 13% of nonolfactory receptors. We broadly surveyed the receptor modifications/engineering and methods used to produce all available GPCR crystal and cryo-electron microscopy (cryo-EM) structures, and present an interactive resource integrated in GPCRdb ( http://www...
January 21, 2019: Nature Methods
Sudipta Ashe, Shweta Yadav
During Drosophila phototransduction, the G protein coupled receptor (GPCR) Rhodopsin (Rh1) transduces photon absorption into electrical signal via G-protein coupled activation of phospholipase C (PLC). Rh1 levels in the plasma membrane are critical for normal sensitivity to light. In this study, we report that Protein kinase D (dPKD) regulates Rh1 homeostasis in adult photoreceptors. Although eye development and retinal structure are unaffected in the dPKD hypomorph (dPKDH ), it exhibited elevated levels of Rh1...
January 21, 2019: Fly
Rory Sleno, Terence E Hébert
How G protein-coupled receptors (GPCR) interact with one another remains an area of active investigation. Obligate dimers of class C GPCRs such as metabotropic GABA and glutamate receptors are well accepted, although whether this is a general feature of other GPCRs is still strongly debated. In this review, we focus on the idea that GPCR dimers and oligomers are better imagined as parts of larger metastable signalling complexes. We discuss the nature of functional oligomeric entities, their stabilities and kinetic features and how structural and functional asymmetries of such metastable entities might have implications for drug discovery...
January 16, 2019: Neuropharmacology
Suzan Fares, Katja Spiess, Emma T B Olesen, Jianmin Zuo, Sarah Jackson, Thomas N Kledal, Mark R Wills, Mette M Rosenkilde
The Epstein-Barr virus (EBV) BILF1 gene encodes a constitutively active G protein-coupled receptor (GPCR) that downregulates major histocompatibility complex (MHC) class I and induces signaling-dependent tumorigenesis. Different BILF1 homologs display highly conserved extracellular loops (ECLs) including the conserved cysteine residues involved in disulfide bridges present in class A GPCRs (GPCR bridge between transmembrane helix 3 [TM-3] and ECL-2) and in chemokine receptors (CKR bridge between the N terminus and ECL-3)...
January 15, 2019: MBio
Anthony Yiu-Ho Woo, Xin-Yue Ge, Li Pan, Gang Xing, Yong-Mei Mo, Rui-Juan Xing, Xiao-Ran Li, Yu-Yang Zhang, Irving W Wainer, Mao-Sheng Cheng, Rui-Ping Xiao
β-Arrestins are a small family of proteins important for signal transduction at G protein-coupled receptors (GPCRs). β-Arrestins are involved in the desensitization of GPCRs. Recently, biased ligands possessing different efficacies in activating the G protein- versus the β-arrestin-dependent signals downstream of a single GPCR have emerged, which can be used to selectively modulate GPCR signal transduction in such a way that desirable signals are enhanced to produce therapeutic effects while undesirable signals of the same GPCR are suppressed to avoid side effects...
January 14, 2019: Acta Pharmacologica Sinica
Kaavya Krishna Kumar, Moran Shalev-Benami, Michael J Robertson, Hongli Hu, Samuel D Banister, Scott A Hollingsworth, Naomi R Latorraca, Hideaki E Kato, Daniel Hilger, Shoji Maeda, William I Weis, David L Farrens, Ron O Dror, Sanjay V Malhotra, Brian K Kobilka, Georgios Skiniotis
Cannabis elicits its mood-enhancing and analgesic effects through the cannabinoid receptor 1 (CB1), a G protein-coupled receptor (GPCR) that signals primarily through the adenylyl cyclase-inhibiting heterotrimeric G protein Gi . Activation of CB1-Gi signaling pathways holds potential for treating a number of neurological disorders and is thus crucial to understand the mechanism of Gi activation by CB1. Here, we present the structure of the CB1-Gi signaling complex bound to the highly potent agonist MDMB-Fubinaca (FUB), a recently emerged illicit synthetic cannabinoid infused in street drugs that have been associated with numerous overdoses and fatalities...
December 21, 2018: Cell
Laura M Wingler, Conor McMahon, Dean P Staus, Robert J Lefkowitz, Andrew C Kruse
The angiotensin II (AngII) type 1 receptor (AT1R) is a critical regulator of cardiovascular and renal function and is an important model for studies of G-protein-coupled receptor (GPCR) signaling. By stabilizing the receptor with a single-domain antibody fragment ("nanobody") discovered using a synthetic yeast-displayed library, we determined the crystal structure of active-state human AT1R bound to an AngII analog with partial agonist activity. The nanobody binds to the receptor's intracellular transducer pocket, stabilizing the large conformational changes characteristic of activated GPCRs...
January 3, 2019: Cell
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