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Gpcr Structure

Abhishek Bandyopadhyay, Ned Van Eps, Bryan T Eger, Sarah Rauscher, Ravikiran S Yedidi, Tina Moroni, Graham M West, Kelly Ann Robinson, Patrick R Griffin, Jane Mitchell, Oliver P Ernst
Photoreceptors of the squid Loligo pealei contain a G-protein-coupled receptor (GPCR) signaling system that activates phospholipase C in response to light. Analogous to the mammalian visual system, signaling of the photoactivated GPCR rhodopsin is terminated by binding of squid arrestin (sArr). sArr forms a light-dependent, high affinity complex with squid rhodopsin, which does not require prior receptor phosphorylation for interaction. This is at odds with classical mammalian GPCR desensitization where an agonist-bound phosphorylated receptor is needed to break stabilizing constraints within arrestins, the so-called 'three-element interaction' and 'polar core' network, before a stable receptor-arrestin complex can be established...
August 15, 2018: Journal of Molecular Biology
Eric A Wold, Jianping Chen, Kathryn A Cunningham, Jia Zhou
G protein-coupled receptors (GPCRs) have been tractable drug targets for decades with over one-third of currently marketed drugs targeting GPCRs. Of these, the class A GPCR superfamily is highly represented and continued drug discovery for this family of receptors may provide novel therapeutics for a vast range of diseases. GPCR allosteric modulation is an innovative targeting approach that broadens the available small molecule toolbox and is proving to be a viable drug discovery strategy, as evidenced by recent FDA approvals and clinical trials...
August 14, 2018: Journal of Medicinal Chemistry
Denise Wootten, Arthur Christopoulos, Maria Marti-Solano, M Madan Babu, Patrick M Sexton
G protein-coupled receptors (GPCRs) are the largest group of cell surface receptors in humans that signal in response to diverse inputs and regulate a plethora of cellular processes. Hence, they constitute one of the primary drug target classes. Progress in our understanding of GPCR dynamics, activation and signalling has opened new possibilities for selective drug development. A key advancement has been provided by the concept of biased agonism, which describes the ability of ligands acting at the same GPCR to elicit distinct cellular signalling profiles by preferentially stabilizing different active conformational states of the receptor...
August 13, 2018: Nature Reviews. Molecular Cell Biology
Michael P Bokoch, Hyunil Jo, James R Valcourt, Yoga Srinivasan, Albert C Pan, Sara Capponi, Michael Grabe, Ron O Dror, David E Shaw, William F DeGrado, Shaun R Coughlin
The pathways that G protein-coupled receptor (GPCR) ligands follow as they bind to or dissociate from their receptors are largely unknown. Protease-activated receptor 1 (PAR1) is a GPCR activated by intramolecular binding of a tethered agonist peptide that is exposed by thrombin cleavage. By contrast, the PAR1 antagonist vorapaxar is a lipophilic drug that binds in a pocket almost entirely occluded from extracellular solvent. The binding and dissociation pathway of vorapaxar is unknown. Starting with the crystal structure of vorapaxar bound to PAR1, we performed temperature-accelerated molecular dynamics simulations of ligand dissociation...
August 13, 2018: Biochemistry
Muzaddid Sarker, Matt Speckert, Jan K Rainey
Apelin peptides are cognate ligands for the apelin receptor, a G-protein coupled receptor (GPCR). The apelinergic system plays critical roles in wide-ranging physiological activities including function and development of the central nervous and cardiovascular systems. Apelin is found in 13-55 residue isoforms in vivo, all of which share the C-terminal portion of the preproapelin precursor. Characterization of high-resolution structures and detergent micelle interactions of apelin-17 led to a two-step membrane-catalyzed binding and GPCR activation mechanism hypothesis recapitulated in longer isoforms...
August 9, 2018: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
Stuart James Mundell, Andrew Mumford
Platelet activity is regulated by a number of surface expressed G protein-coupled receptors (GPCRs) including the α isoform of the thromboxane receptor (TPα receptor). With the advance of genomic technologies, there has been a substantial increase in the identification of naturally occurring rare GPCR variants including in the TBXA2R gene, which encodes the TPα receptor. The study of patients with naturally occurring variants within TBXA2R associated with bleeding and abnormal TPα receptor function has provided a powerful insight in defining the critical role of TPα in thrombus formation...
August 8, 2018: Platelets
Chenyi Liao, Victor May, Jianing Li
Shapeshifters, in common mythology, are entities that can undergo multiple physical transformations. As our understanding of G protein-coupled receptors (GPCRs) has accelerated and been refined over the last two decades, we now understand that GPCRs are not static proteins, but rather dynamic structures capable of moving from one posture to the next, and adopting unique functional characteristics at each transition. This model of GPCR dynamics underlies our current understanding of biased agonism-how different ligands to the same receptor can generate different intracellular signals-and constitutive receptor activity, or the level of unbound basal receptor signaling that can be attenuated by inverse agonists...
August 3, 2018: Journal of Molecular Neuroscience: MN
D Keri, P Barth
The prominence of G protein-coupled receptors (GPCRs) in human physiology and disease has resulted in their intense study in various fields of research ranging from neuroscience to structural biology. With over 800 members in the human genome and their involvement in a myriad of diseases, GPCRs are the single largest family of drug targets, and an ever-present interest exists in further drug discovery and structural characterization efforts. However, low GPCR expression and stability outside the natural lipid environments have challenged these efforts...
July 25, 2018: Current Opinion in Structural Biology
Victor Jun Yu Lim, Weina Du, Yu Zong Chen, Hao Fan
G-protein-coupled receptor (GPCR) is an important target class of proteins for drug discovery, with over 27% of FDA-approved drugs targeting GPCRs. However, being a membrane protein, it is difficult to obtain the 3D crystal structures of GPCRs for virtual screening of ligands by molecular docking. Thus, we evaluated the virtual screening performance of homology models of human GPCRs with respect to the corresponding crystal structures. Among the 19 GPCRs involved in this study, we observed that 10 GPCRs have homology models that have better or comparable performance with respect to the corresponding X-ray structures, making homology models a viable choice for virtual screening...
July 27, 2018: Proteins
Gunnar Schulte, Shane C Wright
For more than 30 years, WNT/β-catenin and planar cell polarity signaling has formed the basis for what we understand to be the primary output of the interaction between WNTs and their cognate receptors known as Frizzleds (FZDs). In the shadow of these pathways, evidence for the involvement of heterotrimeric G proteins in WNT signaling has grown substantially over the years - redefining the complexity of the WNT signaling network. Moreover, the distinct characteristics of FZD paralogs are becoming better understood, and we can now apply concepts valid for classical GPCRs to grasp FZDs as molecular machines at the interface of ligand binding and intracellular effects...
July 23, 2018: Trends in Pharmacological Sciences
José Carlos Gómez Tamayo, Mireia Olivella, Santiago Ríos, Marlous Hoogstraat, Angel Gonzalez, Eduardo Mayol, Xavier Deupi, Mercedes Campillo, Arnau Cordomí
G protein-coupled receptors (GPCRs) are one of the largest protein families in mammals. They mediate signal transduction across cell membranes and are important targets for the pharmaceutical industry. The G Protein-Coupled Receptors-Sequence Analysis and Statistics (GPCR-SAS) web application provides a set of tools to perform comparative analysis of sequence positions between receptors, based on a curated structural-informed multiple sequence alignment. The analysis tools include: (i) percentage of occurrence of an amino acid or motif and entropy at a position or range of positions, (ii) covariance of two positions, (iii) correlation between two amino acids in two positions (or two sequence motifs in two ranges of positions), and (iv) snake-plot representation for a specific receptor or for the consensus sequence of a group of selected receptors...
2018: PloS One
Ismail Erol, Busecan Aksoydan, Isik Kantarcioglu, Serdar Durdagi
G protein-coupled receptors (GPCRs) represent the biggest class of membrane proteins included in signal transduction cascade across the biological lipid bilayers. They are essential target structures for cell signaling and are of great commercial interest to the pharmaceutical industry (~50% of marketed drugs and ~25% of top-selling drugs targeting this receptor family). Recent advances made in molecular biology and computational chemistry open new avenues for the design of new therapeutic compounds. Molecular biology has recently provided the crystal structures of a few ligand-bound GPCRs in active and inactive states, which can be used as accurate templates in modeling studies...
2018: Methods in Molecular Biology
Xiaojing Yuan, Yechun Xu
G protein-coupled receptors represent the largest family of human membrane proteins and are modulated by a variety of drugs and endogenous ligands. Molecular modeling techniques, especially enhanced sampling methods, have provided significant insight into the mechanism of GPCR⁻ligand recognition. Notably, the crucial role of the membrane in the ligand-receptor association process has earned much attention. Additionally, docking, together with more accurate free energy calculation methods, is playing an important role in the design of novel compounds targeting GPCRs...
July 20, 2018: International Journal of Molecular Sciences
Ashref El Buri, David R Adams, Douglas Smith, Rothwelle J Tate, Margaret Mullin, Susan Pyne, Nigel J Pyne
We demonstrate here that the G protein-coupled receptor (GPCR), sphingosine 1-phosphate receptor 2 (S1P2 , Mr = 40 kDa) is shed in hsp70+ and CD63+ containing exosomes from MDA-MB-231 breast cancer cells. The receptor is taken up by fibroblasts, where it is N-terminally processed to a shorter form (Mr = 36 kDa) that appears to be constitutively active and able to stimulate the extracellular signal regulated kinase-1/2 (ERK-1/2) pathway and DNA synthesis. An N-terminally truncated construct of S1P2 , which may correspond to the processed form of the receptor generated in fibroblasts, was found to be constitutively active when over-expressed in HEK293 cells...
June 29, 2018: Oncotarget
Claudie Lefort, Lauriane Benoist, Stéphanie Chadet, Marie Piollet, Audrey Heraud, Dominique Babuty, Christophe Baron, Fabrice Ivanes, Denis Angoulvant
Cardiac fibroblasts are important regulators of myocardial structure and function. Their implications in pathological processes such as Ischemia/Reperfusion are well characterized. Cardiac fibroblasts respond to stress by excessive proliferation and secretion of pro-inflammatory cytokines and other factors, e.g. ATP, leading to purinergic receptors activation. P2Y11 receptor (P2Y11R) is an ATP-sensitive GPCR playing an immunomodulatory role in human dendritic cells (DC). We hypothesized that P2Y11R stimulation modulated the pro-inflammatory responses of human cardiac fibroblasts (HCF) to Hypoxia/Reoxygenation (H/R) mainly by acting on their secretome...
July 20, 2018: Journal of Molecular and Cellular Cardiology
Li Liu, Stefanie Boyd, Mehraban Kavoussi, Lee A Bulla, Duane D Winkler
The Cry1Ab toxin produced by Bacillus thuringiensis binds to a conserved structural motif in the 12th ectodomain module (EC12) of BT-R1 , a cadherin G protein-coupled receptor (GPCR) contained in the membrane of midgut epithelial cells of the tobacco hornworm Manduca sexta . Toxin binding transmits a signal into the cells and turns on a multi-step signal transduction pathway, culminating in cell death. Using chromatographically purified Cry1Ab and EC12 proteins, we demonstrated the direct formation of a stable complex between these two proteins in solution and visualized it on a native polyacrylamide gel...
2018: Journal of Proteomics & Bioinformatics
Fatma H Al-Awadhi, Bowen Gao, Mohammad A Rezaei, Jason C Kwan, Chenglong Li, Tao Ye, Valerie J Paul, Hendrik Luesch
Five novel modified linear peptides named brintonamides A-E (1-5) were discovered from a marine cyanobacterial sample collected from Brinton Channel, Florida Keys. The total synthesis of 1-5 in addition to two other structurally related analogues (6 and 7) was achieved, which provided more material to allow rigorous biological evaluation and SAR studies. Compounds were subjected to cancer-focused phenotypic cell viability and migration assays and orthogonal target-based pharmacological screening platforms to identify their protease and GPCR modulatory activity profiles...
July 26, 2018: Journal of Medicinal Chemistry
Sae Ryun Ahn, Ji Hyun An, Il Ha Jang, Wonjoo Na, Heehong Yang, Kyung Hee Cho, Sang Hun Lee, Hyun Seok Song, Jyongsik Jang, Tai Hyun Park
Numerous efforts have been made to measure tastes for various purposes. However, most taste information is still obtained by human sensory evaluation. It is difficult to quantify a degree of taste or establish taste standard. Although artificial taste sensors called electronic tongues utilizing synthetic materials such as polymers, semiconductors, or lipid membranes have been developed, they have limited performance due to their low sensitivity and specificity. Recently, bioelectronic tongues fabricated by integrating human taste receptors and nanomaterial-based sensor platforms have been found to have high performance for measuring tastes with human-like taste perception...
June 18, 2018: Biosensors & Bioelectronics
Qiansen Zhang, Mang Zhou, Lifen Zhao, Hualiang Jiang, Huaiyu Yang
G protein-coupled receptors (GPCRs) make up the largest family of drug targets. The second extracellular loop (ECL2) and extracellular end of the third transmembrane helix (TM3) are basic structural elements of the GPCR ligand binding site. Currently, the disulfide bond between the two conserved cysteines in the ECL2 and TM3 is considered to be a basic GPCR structural feature. This disulfide bond has a significant effect on receptor dynamics and ligand binding. Here, molecular dynamics simulations and experimental results show that the two cysteines are distant from one another in the highest-population conformational state of ligand-free class A GPCRs and do not form a disulfide bond, indicating that the dynamics of the GPCR extracellular side are different from our conventional understanding...
July 24, 2018: Biochemistry
Francesco De Pascali, Eric Reiter
Gonadotropin receptors include the follicle stimulating hormone receptor (FSHR) and the luteinizing hormone/choriogonadotropin receptor (LHCGR), both belong to the G protein- coupled receptor (GPCR) superfamily and being essential to reproduction. FSHR is activated by follicle stimulating hormone (FSH) while LHCGR is activated by either luteinizing hormone (LH) or choriogonadotropin (CG). Upon ligand binding, gonadotropin receptors undergo conformational changes that leads to the activation of the heterotrimeric G protein, resulting in the production of different second messengers...
July 10, 2018: Minerva Ginecologica
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