DE-ORPHAN SIGNED
DEtermination of Orphan Receptor PHysiological Agonists and sigNals
Total Cost €
0EC-Contrib. €
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Project "DE-ORPHAN" data sheet
The following table provides information about the project.
| Coordinator |
KOBENHAVNS UNIVERSITET
Organization address contact info |
| 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.
| # | ||||
|---|---|---|---|---|
| 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 |
|---|---|---|---|
| 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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