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Genome-Wide Prediction of Small Molecule Binding to Remote
bioRxiv preprint doi: https://doi.org/10.1101/2020.08.04.236729; this version posted August 5, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Genome-wide Prediction of Small Molecule Binding 2 to Remote Orphan Proteins Using Distilled Sequence 3 Alignment Embedding 1 2 3 4 4 Tian Cai , Hansaim Lim , Kyra Alyssa Abbu , Yue Qiu , 5,6 1,2,3,4,7,* 5 Ruth Nussinov , and Lei Xie 1 6 Ph.D. Program in Computer Science, The Graduate Center, The City University of New York, New York, 10016, USA 2 7 Ph.D. Program in Biochemistry, The Graduate Center, The City University of New York, New York, 10016, USA 3 8 Department of Computer Science, Hunter College, The City University of New York, New York, 10065, USA 4 9 Ph.D. Program in Biology, The Graduate Center, The City University of New York, New York, 10016, USA 5 10 Computational Structural Biology Section, Basic Science Program, Frederick National Laboratory for Cancer Research, 11 Frederick, MD 21702, USA 6 12 Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel 13 Aviv, Israel 7 14 Helen and Robert Appel Alzheimer’s Disease Research Institute, Feil Family Brain & Mind Research Institute, Weill 15 Cornell Medicine, Cornell University, New York, 10021, USA * 16 [email protected] 17 July 27, 2020 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.08.04.236729; this version posted August 5, 2020. -
Edinburgh Research Explorer
Edinburgh Research Explorer International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list Citation for published version: Davenport, AP, Alexander, SPH, Sharman, JL, Pawson, AJ, Benson, HE, Monaghan, AE, Liew, WC, Mpamhanga, CP, Bonner, TI, Neubig, RR, Pin, JP, Spedding, M & Harmar, AJ 2013, 'International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands', Pharmacological reviews, vol. 65, no. 3, pp. 967-86. https://doi.org/10.1124/pr.112.007179 Digital Object Identifier (DOI): 10.1124/pr.112.007179 Link: Link to publication record in Edinburgh Research Explorer Document Version: Publisher's PDF, also known as Version of record Published In: Pharmacological reviews Publisher Rights Statement: U.S. Government work not protected by U.S. copyright General rights Copyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. Take down policy The University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorer content complies with UK legislation. If you believe that the public display of this file breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 02. Oct. 2021 1521-0081/65/3/967–986$25.00 http://dx.doi.org/10.1124/pr.112.007179 PHARMACOLOGICAL REVIEWS Pharmacol Rev 65:967–986, July 2013 U.S. -
Investigation of Candidate Genes and Mechanisms Underlying Obesity
Prashanth et al. BMC Endocrine Disorders (2021) 21:80 https://doi.org/10.1186/s12902-021-00718-5 RESEARCH ARTICLE Open Access Investigation of candidate genes and mechanisms underlying obesity associated type 2 diabetes mellitus using bioinformatics analysis and screening of small drug molecules G. Prashanth1 , Basavaraj Vastrad2 , Anandkumar Tengli3 , Chanabasayya Vastrad4* and Iranna Kotturshetti5 Abstract Background: Obesity associated type 2 diabetes mellitus is a metabolic disorder ; however, the etiology of obesity associated type 2 diabetes mellitus remains largely unknown. There is an urgent need to further broaden the understanding of the molecular mechanism associated in obesity associated type 2 diabetes mellitus. Methods: To screen the differentially expressed genes (DEGs) that might play essential roles in obesity associated type 2 diabetes mellitus, the publicly available expression profiling by high throughput sequencing data (GSE143319) was downloaded and screened for DEGs. Then, Gene Ontology (GO) and REACTOME pathway enrichment analysis were performed. The protein - protein interaction network, miRNA - target genes regulatory network and TF-target gene regulatory network were constructed and analyzed for identification of hub and target genes. The hub genes were validated by receiver operating characteristic (ROC) curve analysis and RT- PCR analysis. Finally, a molecular docking study was performed on over expressed proteins to predict the target small drug molecules. Results: A total of 820 DEGs were identified between -
G Protein-Coupled Receptors
S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors. British Journal of Pharmacology (2015) 172, 5744–5869 THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: G protein-coupled receptors Stephen PH Alexander1, Anthony P Davenport2, Eamonn Kelly3, Neil Marrion3, John A Peters4, Helen E Benson5, Elena Faccenda5, Adam J Pawson5, Joanna L Sharman5, Christopher Southan5, Jamie A Davies5 and CGTP Collaborators 1School of Biomedical Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK, 2Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK, 3School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, UK, 4Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK, 5Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/ 10.1111/bph.13348/full. G protein-coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. -
Multi-Functionality of Proteins Involved in GPCR and G Protein Signaling: Making Sense of Structure–Function Continuum with In
Cellular and Molecular Life Sciences (2019) 76:4461–4492 https://doi.org/10.1007/s00018-019-03276-1 Cellular andMolecular Life Sciences REVIEW Multi‑functionality of proteins involved in GPCR and G protein signaling: making sense of structure–function continuum with intrinsic disorder‑based proteoforms Alexander V. Fonin1 · April L. Darling2 · Irina M. Kuznetsova1 · Konstantin K. Turoverov1,3 · Vladimir N. Uversky2,4 Received: 5 August 2019 / Revised: 5 August 2019 / Accepted: 12 August 2019 / Published online: 19 August 2019 © Springer Nature Switzerland AG 2019 Abstract GPCR–G protein signaling system recognizes a multitude of extracellular ligands and triggers a variety of intracellular signal- ing cascades in response. In humans, this system includes more than 800 various GPCRs and a large set of heterotrimeric G proteins. Complexity of this system goes far beyond a multitude of pair-wise ligand–GPCR and GPCR–G protein interactions. In fact, one GPCR can recognize more than one extracellular signal and interact with more than one G protein. Furthermore, one ligand can activate more than one GPCR, and multiple GPCRs can couple to the same G protein. This defnes an intricate multifunctionality of this important signaling system. Here, we show that the multifunctionality of GPCR–G protein system represents an illustrative example of the protein structure–function continuum, where structures of the involved proteins represent a complex mosaic of diferently folded regions (foldons, non-foldons, unfoldons, semi-foldons, and inducible foldons). The functionality of resulting highly dynamic conformational ensembles is fne-tuned by various post-translational modifcations and alternative splicing, and such ensembles can undergo dramatic changes at interaction with their specifc partners. -
G Protein‐Coupled Receptors
S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2019/20: G protein-coupled receptors. British Journal of Pharmacology (2019) 176, S21–S141 THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: G protein-coupled receptors Stephen PH Alexander1 , Arthur Christopoulos2 , Anthony P Davenport3 , Eamonn Kelly4, Alistair Mathie5 , John A Peters6 , Emma L Veale5 ,JaneFArmstrong7 , Elena Faccenda7 ,SimonDHarding7 ,AdamJPawson7 , Joanna L Sharman7 , Christopher Southan7 , Jamie A Davies7 and CGTP Collaborators 1School of Life Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK 2Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria 3052, Australia 3Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK 4School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK 5Medway School of Pharmacy, The Universities of Greenwich and Kent at Medway, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB, UK 6Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK 7Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. -
Two Neuroendocrine G Protein‐Coupled Receptor Molecules, Somatostatin and Melatonin: Physiology of Signal Transduction and Therapeutic Perspectives
Received: 7 August 2020 | Revised: 4 September 2020 | Accepted: 10 September 2020 DOI: 10.1002/jcp.30062 REVIEW ARTICLE Two neuroendocrine G protein‐coupled receptor molecules, somatostatin and melatonin: Physiology of signal transduction and therapeutic perspectives Eva Costanzi1 | Carolina Simioni2,3 | Ilaria Conti1 | Ilaria Laface1 | Gabriele Varano1 | Cinzia Brenna1 | Luca M. Neri1,3 1Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Abstract Ferrara, Italy Recent studies have shown that G protein‐coupled receptors (GPCRs), the largest 2Department of Medical Sciences, University signal‐conveying receptor family, are targets for mutations occurring frequently in of Ferrara, Ferrara, Italy 3Laboratory for Technologies of Advanced different cancer types. GPCR alterations associated with cancer development re- Therapies (LTTA)‐Electron Microscopy present significant challenges for the discovery and the advancement of targeted Center, University of Ferrara, Ferrara, Italy therapeutics. Among the different molecules that can activate GPCRs, we focused Correspondence on two molecules that exert their biological actions regulating many typical features Luca M. Neri, Department of Morphology, of tumorigenesis such as cellular proliferation, survival, and invasion: somatostatin Surgery and Experimental Medicine, University of Ferrara, Via Fossato di Mortara and melatonin. The modulation of signaling pathways, that involves these two 70, Ferrara 44121, Italy. molecules, opens an interesting scenario for cancer therapy, with the opportunity to Email: [email protected] act at different molecular levels. Therefore, the aim of this review is the analysis of the biological activity and the therapeutic potential of somatostatin and melatonin, displaying a high affinity for GPCRs, that interfere with cancer development and maintenance. KEYWORDS GPCRs, melatonin, somatostatin, targeted therapies, tumors 1 | INTRODUCTION "G protein" identifies a complex of three proteins, named alpha, beta and gamma. -
Orphan G Protein Coupled Receptors in Affective Disorders
G C A T T A C G G C A T genes Review Orphan G Protein Coupled Receptors in Affective Disorders Lyndsay R. Watkins and Cesare Orlandi * Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642, USA; [email protected] * Correspondence: [email protected] Received: 3 June 2020; Accepted: 21 June 2020; Published: 24 June 2020 Abstract: G protein coupled receptors (GPCRs) are the main mediators of signal transduction in the central nervous system. Therefore, it is not surprising that many GPCRs have long been investigated for their role in the development of anxiety and mood disorders, as well as in the mechanism of action of antidepressant therapies. Importantly, the endogenous ligands for a large group of GPCRs have not yet been identified and are therefore known as orphan GPCRs (oGPCRs). Nonetheless, growing evidence from animal studies, together with genome wide association studies (GWAS) and post-mortem transcriptomic analysis in patients, pointed at many oGPCRs as potential pharmacological targets. Among these discoveries, we summarize in this review how emotional behaviors are modulated by the following oGPCRs: ADGRB2 (BAI2), ADGRG1 (GPR56), GPR3, GPR26, GPR37, GPR50, GPR52, GPR61, GPR62, GPR88, GPR135, GPR158, and GPRC5B. Keywords: G protein coupled receptor (GPCR); G proteins; orphan GPCR (oGPCR); mood disorders; major depressive disorder (MDD); bipolar disorder (BPD); anxiety disorders; antidepressant; animal models 1. Introduction Mood alterations due to pharmacological treatments that modulate serotonergic and noradrenergic systems laid the foundations for the monoamine hypothesis that has led research on mood disorders since the late 1950s [1–3]. Dopaminergic alterations have also been associated with major depressive disorder (MDD) symptoms, such as anhedonia [4]. -
G Protein‐Coupled Receptors
S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2019/20: G protein-coupled receptors. British Journal of Pharmacology (2019) 176, S21–S141 THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: G protein-coupled receptors Stephen PH Alexander1 , Arthur Christopoulos2 , Anthony P Davenport3 , Eamonn Kelly4, Alistair Mathie5 , John A Peters6 , Emma L Veale5 ,JaneFArmstrong7 , Elena Faccenda7 ,SimonDHarding7 ,AdamJPawson7 , Joanna L Sharman7 , Christopher Southan7 , Jamie A Davies7 and CGTP Collaborators 1School of Life Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK 2Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria 3052, Australia 3Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK 4School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK 5Medway School of Pharmacy, The Universities of Greenwich and Kent at Medway, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB, UK 6Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK 7Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. -
RT² Profiler PCR Array (384-Well Format) Mouse G Protein Coupled Receptors 384HT
RT² Profiler PCR Array (384-Well Format) Mouse G Protein Coupled Receptors 384HT Cat. no. 330231 PAMM-3009ZE For pathway expression analysis Format For use with the following real-time cyclers RT² Profiler PCR Array, Applied Biosystems® models 7900HT (384-well block), Format E ViiA™ 7 (384-well block); Bio-Rad CFX384™ RT² Profiler PCR Array, Roche® LightCycler® 480 (384-well block) Format G Description The Mouse G Protein Coupled Receptors 384HT RT² Profiler™ PCR Array profiles the expression of a comprehensive panel of 370 genes encoding the most important G Protein Coupled Receptors (GPCR). GPCR regulate a number of normal biological processes and play roles in the pathophysiology of many diseases upon dysregulation of their downstream signal transduction activities. As a result, they represent 30 percent of the targets for all current drug development. Developing drug screening assays requires a survey of which GPCR the chosen cell-based model system expresses, to determine not only the expression of the target GPCR, but also related GPCR to assess off-target side effects. Expression of other unrelated GPCR (even orphan receptors whose ligand are unknown) may also correlate with off-target side effects. The ligands that bind and activate the receptors on this array include neurotransmitters and neuropeptides, hormones, chemokines and cytokines, lipid signaling molecules, light-sensitive compounds, and odorants and pheromones. The normal biological processes regulated by GPCR include, but are not limited to, behavioral and mood regulation (serotonin, dopamine, GABA, glutamate, and other neurotransmitter receptors), autonomic (sympathetic and parasympathetic) nervous system transmission (blood pressure, heart rate, and digestive processes via hormone receptors), inflammation and immune system regulation (chemokine receptors, histamine receptors), vision (opsins like rhodopsin), and smell (olfactory receptors for odorants and vomeronasal receptors for pheromones). -
Introduction
GPCR Introduction G protein-coupled receptors (GPCRs) are the GPCRs Super-Family largest family of transmembrane receptors and are 375 GPCR Drug Targets, 225 with Known Ligands, 150 Orphan Targets responsible for the transduction of a diverse range of extracellular signals. The range of physiological processes mediated by GPCRs makes them one GRM7 GRM8 GLUTAMATE (15) SECRETIN GRM2 FZD7 TAS1R3 FZD2 of the most important classes of proteins for drug (15) GRM4 GRM3 TAS1R1FZD1 GLP2R GIPR GRM6 GRPC6A FRIZZED/TAS2 discovery. ADHESION GLP1R GCGR GRM5 FZD3 PTHR2 GRM1 (24) LEC1 VIPR2 PTHR1 (24) TAS1R2 FZD6 LEC2 TAS2R13 CELSR2PACAP FZD8 The study of GPCRs may involve ligand binding, G CRHR2 FZD5 TAS2R16 TAS2R14 CALCRL LEC3 VIPR1 CRHR1 CASR GABBR2 FZD10 TAS2R1 TAS2R10 EMR3EMR2 CELSR3 BAI2 CALCR FZD4 TAS2R5 TAS2R3 SCTR FZD9 protein activation, internalization, and downstream ETL BAI3 GPR60 TAS2R9 CELSR1 GHRHR GABBR1 GPR59 TAS2R8 TAS2R4 TAS2R7 EMR1 BAI1 SMOH CXCR3 second messenger events. Each step of the CXCR5 CCR11 CXCR2 CD97 SSTR1 SSTR3 CCR10 CCR6 SSTR5 CXCR1 GPR111 CXCR6 pathway offers an opportunity to exploit the full SSTR2 CCR9 GPR115 SSTR4 CCR7 GPR116 GPR112 GPR8 CCRL2 GPR113 GPR7 CXC3R1CCR8 therapeutic potential of targeting GPCRs. GPR110 CCR4 HE6 NTSR2 CCR1 TM7XN1 GPR114 NMU1R GPR54 GALR1 CCBP2 GHSR GALR2 RDC1 CCR3 GPR97 NPY1R XCR1 PPYR1 NMU2R MTLR MCHR1 GALR3 ADMR NPY2R AGTR1 TACR3 UR2R MCHR2 AGTRL1 AGTR2 CCR5 TAC3RL PrRP γ GPR26 BDKRB2 CCR2 GRM7 GRM8 GLUTAMATE (15) TACR1 TACR2 GRP72 OR1A1 SALPR OLFACTORY GPR15 NPFF1 NPY5R OR1D2 (388) GPTH2 -
Brain Cell Type Proportion Analysis Using BRETIGEA
Brain cell type proportion analysis using BRETIGEA Andrew McKenzie, Minghui Wang, Bin Zhang 2021-05-04 Contents 1 Background for BRETIGEA 1 2 Introduction to BRETIGEA 2 3 Data loading and input format 2 4 Relative cell type proportion estimation 2 4.1 Selecting the nMarker parameter . .6 5 Using alternative cell type marker genes from Kelley et al. 12 6 Using your own cell type marker genes 20 7 Adjusting bulk gene expression data for estimated cell type proportions 24 8 Help and other resources 28 1 Background for BRETIGEA Several comprehensive RNA-seq experiments in different brain cell types have now been published in humans and mice. Some of these experiments have profiled gene expression of cell populations isolated through immunopanning procedures. Immunopanning involves immunoprecipitation of particular cell types in cell culture plates, based on selection for an antibody adsorbed to the plate surface. Others studies have performed RNA profiling of single cells with microfluidics devices and used clustering methods to identify cell types from the resulting RNA expression profiles. The devices used for single cell RNA sequencing (scRNA-seq) often select cells based on size or via encapsulation in a droplet and involve the creation of a cDNA library from the transcriptome from a theoretical maximum of one cell. Existing studies have been mainly based on individual datasets, and are therefore subject to systematic noise, including sampling bias due to sample collection or preparation technique, as well as stochasticity in gene expression. As an increasing number of RNA-seq cell type-specific transcriptomic experiments have become available for both human and mouse, we set out to conduct a comprehensive meta-analysis of brain cell type gene signatures, which is now published in McKenzie et al (2018), doi:10.1038/s41598-018-27293-5.