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DE-ORPHAN SIGNED

DEtermination of Orphan Receptor PHysiological Agonists and sigNals

Total Cost €

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EC-Contrib. €

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Partnership

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 DE-ORPHAN project word cloud

Explore the words cloud of the DE-ORPHAN project. It provides you a very rough idea of what is the project "DE-ORPHAN" about.

human    coupled    receptors    simultaneously    throughput    interdisciplinary    independently    close    innovative    signaling    druggable    insights    tool    ligands    gq    dissection    de    multiple    libraries    computational    networks    crystal    data    handpicking    candidate    screening    orphanization    13    membrane    compounds    fewer    g12    acting    structural    receptor    breakthroughs    first    inhibitors    largely    physiological    witness    bioinformatics    analyze    drug    peptide    drugs    complementary    concert    agonists    protein    context    technique    applies    introduce    designed    aka    mechanisms    families    characterization    optimization    pharmacology    failed    hypotheses    functional    ligand    place    functions    re    employing    structure    orphans    efficient    gs    therapeutic    strategy    medicine    similarities    inhibitor    sequences    biological    selective    orphan    chemoinformatic    bias    relationships    genomic    potent    pharmacological    founded   

Project "DE-ORPHAN" data sheet

The following table provides information about the project.

Coordinator
KOBENHAVNS UNIVERSITET 

Organization address
address: NORREGADE 10
city: KOBENHAVN
postcode: 1165
website: www.ku.dk

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country Denmark [DK]
 Project website http://drug.ku.dk/research/biostructural_research/g_protein_coupled_receptors/orphan_receptor_characterisation/
 Total cost 1˙499˙926 €
 EC max contribution 1˙499˙926 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2014-STG
 Funding Scheme ERC-STG
 Starting year 2015
 Duration (year-month-day) from 2015-05-01   to  2020-04-30

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    KOBENHAVNS UNIVERSITET DK (KOBENHAVN) coordinator 1˙499˙926.00

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 Project objective

G protein-coupled receptors make up both the largest membrane protein and drug target families. DE-ORPHAN aims to determine the close functional context; specifically physiological agonists and signaling pathways; and provide the first research tool compounds, of orphan peptide receptors.

Determination of physiological agonists (aka de-orphanization), by high-throughput screening has largely failed. We will introduce a new research strategy: 1) developing highly innovative bioinformatics methods for handpicking of all orphan receptor targets and candidate ligand screening libraries; and 2) employing a screening technique that can measure all signaling pathways simultaneously.

The first potent and selective pharmacological tool compounds will be identified by chemoinformatic design of focused screening libraries. We will establish the ligands’ structure-activity relationships important for biological activity and further optimization towards drugs.

The first potent and selective Gs- and G12/13 protein inhibitors will be designed by structure-based re-optimization from a recent crystal structure of a Gq-inhibitor complex, and applied to determine orphan receptor signaling pathways and ligand pathway-bias. They will open up for efficient dissection of important signaling networks and development of drugs with fewer side effects.

DE-ORPHANs design hypotheses are based on unique computational methods to analyze protein and ligand similarities and are founded on genomic and protein sequences, structural data and ligands. The interdisciplinary research strategy applies multiple ligands acting independently but in concert to provide complementary receptor characterization. The results will allow the research field to advance into studies of receptor functions and exploitation of druggable targets, ligands and mechanisms. Which physiological insights and therapeutic breakthroughs will we witness when these receptors find their place in human pharmacology and medicine?

 Publications

year authors and title journal last update
List of publications.
2019 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
An online resource for GPCR structure determination and analysis
published pages: 151-162, ISSN: 1548-7091, DOI: 10.1038/s41592-018-0302-x
Nature Methods 16/2 2019-11-25
2019 Simon R. Foster, Alexander S. Hauser, Line Vedel, Ryan T. Strachan, Xi-Ping Huang, Ariana C. Gavin, Sushrut D. Shah, Ajay P. Nayak, Linda M. Haugaard-Kedström, Raymond B. Penn, Bryan L. Roth, Hans Bräuner-Osborne, David E. Gloriam
Discovery of Human Signaling Systems: Pairing Peptides to G Protein-Coupled Receptors
published pages: 895-908.e21, ISSN: 0092-8674, DOI: 10.1016/j.cell.2019.10.010
Cell 179/4 2019-11-18
2019 Amanda E. Mackenzie, Tezz Quon, Li-Chiung Lin, Alexander S. Hauser, Laura Jenkins, Asuka Inoue, Andrew B. Tobin, David E. Gloriam, Brian D. Hudson, Graeme Milligan
Receptor selectivity between the G proteins Gα 12 and Gα 13 is defined by a single leucine-to-isoleucine variation
published pages: 5005-5017, ISSN: 0892-6638, DOI: 10.1096/fj.201801956r
The FASEB Journal 33/4 2019-11-18
2019 Anne Cathrine Nøhr, Mohamed A. Shehata, Daniel Palmer, Rina Pokhrel, Maria Vallianou, Simon R. Foster, Patrick R. Gentry, David E. Gloriam, Hans Bräuner-Osborne
Identification of a novel scaffold for a small molecule GPR139 receptor agonist
published pages: , ISSN: 2045-2322, DOI: 10.1038/s41598-019-40085-9
Scientific Reports 9/1 2019-11-18
2016 Kasper Harpsøe, Michael W. Boesgaard, Christian Munk, Hans Bräuner-Osborne, David E. Gloriam
Structural insight to mutation effects uncover a common allosteric site in class C GPCRs
published pages: btw784, ISSN: 1367-4803, DOI: 10.1093/bioinformatics/btw784
Bioinformatics 2019-05-29
2017 Anne Cathrine Nøhr, Willem Jespers, Mohamed A. Shehata, Leonard Floryan, Vignir Isberg, Kirsten Bayer Andersen, Johan Åqvist, Hugo Gutiérrez-de-Terán, Hans Bräuner-Osborne, David E. Gloriam
The GPR139 reference agonists 1a and 7c, and tryptophan and phenylalanine share a common binding site
published pages: , ISSN: 2045-2322, DOI: 10.1038/s41598-017-01049-z
Scientific Reports 7/1 2019-05-29
2016 Xiao-Feng Xiong, Hang Zhang, Christina R. Underwood, Kasper Harpsøe, Thomas J. Gardella, Mie F. Wöldike, Michael Mannstadt, David E. Gloriam, Hans Bräuner-Osborne, Kristian Strømgaard
Total synthesis and structure–activity relationship studies of a series of selective G protein inhibitors
published pages: 1035-1041, ISSN: 1755-4330, DOI: 10.1038/nchem.2577
Nature Chemistry 8/11 2019-05-29
2017 Gáspár Pándy-Szekeres, Christian Munk, Tsonko M Tsonkov, Stefan Mordalski, Kasper Harpsøe, Alexander S Hauser, Andrzej J Bojarski, David E Gloriam
GPCRdb in 2018: adding GPCR structure models and ligands
published pages: D440-D446, ISSN: 0305-1048, DOI: 10.1093/nar/gkx1109
Nucleic Acids Research 46/D1 2019-05-29
2017 Alexander S. Hauser, Misty M. Attwood, Mathias Rask-Andersen, Helgi B. Schiöth, David E. Gloriam
Trends in GPCR drug discovery: new agents, targets and indications
published pages: 829-842, ISSN: 1474-1776, DOI: 10.1038/nrd.2017.178
Nature Reviews Drug Discovery 16/12 2019-05-29
2015 Kasper Harpsøe, Vignir Isberg, Benjamin G. Tehan, Dahlia Weiss, Angela Arsova, Fiona H. Marshall, Hans Bräuner-Osborne, David E. Gloriam
Selective Negative Allosteric Modulation Of Metabotropic Glutamate Receptors – A Structural Perspective of Ligands and Mutants
published pages: , ISSN: 2045-2322, DOI: 10.1038/srep13869
Scientific Reports 5/1 2019-05-29
2016 Christian Munk, Kasper Harpsøe, Alexander S Hauser, Vignir Isberg, David E Gloriam
Integrating structural and mutagenesis data to elucidate GPCR ligand binding
published pages: 51-58, ISSN: 1471-4892, DOI: 10.1016/j.coph.2016.07.003
Current Opinion in Pharmacology 30 2019-05-29
2016 Anne Cathrine Nøhr, Mohamed A. Shehata, Alexander S. Hauser, Vignir Isberg, Jacek Mokrosinski, I. Sadaf Farooqi, Daniel Sejer Pedersen, David E. Gloriam, Hans Bräuner-Osborne
The orphan G protein-coupled receptor GPR139 is activated by the peptides: Adrenocorticotropic hormone (ACTH), α-, and β-melanocyte stimulating hormone (α-MSH, and β-MSH), and the conserved core motif HFRW
published pages: , ISSN: 0197-0186, DOI: 10.1016/j.neuint.2016.11.012
Neurochemistry International 2019-05-29
2016 C Munk, V Isberg, S Mordalski, K Harpsøe, K Rataj, A S Hauser, P Kolb, A J Bojarski, G Vriend, D E Gloriam
GPCRdb: the G protein-coupled receptor database - an introduction
published pages: 2195-2207, ISSN: 0007-1188, DOI: 10.1111/bph.13509
British Journal of Pharmacology 173/14 2019-05-29
2018 Alexander S. Hauser, Sreenivas Chavali, Ikuo Masuho, Leonie J. Jahn, Kirill A. Martemyanov, David E. Gloriam, M. Madan Babu
Pharmacogenomics of GPCR Drug Targets
published pages: 41-54.e19, ISSN: 0092-8674, DOI: 10.1016/j.cell.2017.11.033
Cell 172/1-2 2019-05-29
2017 Simon R. Foster, Hans Bräuner-Osborne
Investigating Internalization and Intracellular Trafficking of GPCRs: New Techniques and Real-Time Experimental Approaches
published pages: , ISSN: , DOI: 10.1007/164_2017_57
Handbook of Experimental Pharmacology 2019-05-29
2016 Shehata MA, Nøhr AC, Lissa D, Bisig C, Isberg V, Andersen KB, Harpsøe K, Björkling F, Bräuner-Osborne H, Gloriam DE
Novel Agonist Bioisosteres and Common Structure-Activity Relationships for The Orphan G Protein-Coupled Receptor GPR139
published pages: , ISSN: 2045-2322, DOI: 10.1038/srep36681
Scientific Reports 2019-05-29
2016 Vignir Isberg, Stefan Mordalski, Christian Munk, Krzysztof Rataj, Kasper Harpsøe, Alexander S. Hauser, Bas Vroling, Andrzej J. Bojarski, Gert Vriend, David E. Gloriam
GPCRdb: an information system for G protein-coupled receptors
published pages: D356-D364, ISSN: 0305-1048, DOI: 10.1093/nar/gkv1178
Nucleic Acids Research 44/D1 2019-05-29
2017 Hanna B. Christensen, David E. Gloriam, Daniel Sejer Pedersen, Jack B. Cowland, Niels Borregaard, Hans Bräuner-Osborne
Applying label-free dynamic mass redistribution assay for studying endogenous FPR1 receptor signalling in human neutrophils
published pages: 72-78, ISSN: 1056-8719, DOI: 10.1016/j.vascn.2017.07.003
Journal of Pharmacological and Toxicological Methods 88 2019-05-29
2017 Tilman Flock, Alexander S. Hauser, Nadia Lund, David E. Gloriam, Santhanam Balaji, M. Madan Babu
Selectivity determinants of GPCR–G-protein binding
published pages: 317-322, ISSN: 0028-0836, DOI: 10.1038/nature22070
Nature 545/7654 2019-05-29

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