Orphan receptor characterisation – University of Copenhagen

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Department of Drug Design and Pharmacology > Research > Biostructural Research > Gloriam Group > Orphan receptor charac...

Orphan Receptor Characterisation

De-orphanisation

Left) About one third of the human GPCRs are so called orphan receptors, meaning that their endogenous agonist (and function) is unknown. Characterisation of orphan receptors can unravel unknown physiological signalling systems and present new druggable targets, ligands and mechanisms. Right) We apply computational methods to identify; endogenous agonists (orange) that link the receptor to a physiological system, tool compounds (pink) for pharmacological characterisation, and G protein inhibitors (yellow) for effective dissection of the intracellular signalling pathways.

The mapping of the human genome sequence was quickly followed by the bioinformatic identification of a large number of novel GPCR genes, including 24 receptors found by Gloriam and colleagues. Recently, we were the first to identify putative endogenous agonists (L-Trp and L-Phe) for GPR139, antagonists for GPRC6A and agonists for GPR32 and GPR132. Starting early 2015, two large projects funded by Lundbeck Foundation Fellow and ERC Starting Grants initiated 7 and 5-year programmes, respectively, to characterise orphan receptors from in silico to in vivo.

The work is conducted in close collaborations with several groups at the Department of Drug Design and Pharmacology. The Molecular Pharmacology group evaluates and applies receptor ligands in vitro, and also conducts functional studies for selected orphan receptors by applying genetically modified mice and disease models. The Chemical Biology group synthesizes G protein inhibitors that can be used to dissect the intracellular signalling pathways of GPCRs more effectively. The Biostructural Research Section (Gloriam, Gajhede and Kastrup groups) will crystallise de-orphanised receptors in complex with key ligands.

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Selected publications

G protein inhibitors
Xiong XF, Zhang H, Underwood CR, Harpsøe K, Gardella TJ, Wöldike MF, Mannstadt M, Gloriam DE, Bräuner-Osborne H, Strømgaard K.
Total synthesis and structure-activity relationship studies of a series of selective G protein inhibitors.
Nat Chem. 2016 Nov;8(11):1035-1041

Identification of putative endogenous agonists
Nøhr AC, Shehata MA, Hauser AS, Isberg V, Mokrosinski J, Andersen KB, Farooqi 
IS, Pedersen DS, Bräuner-Osborne H#, Gloriam DE#
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.
Neurochem Int. 2017 Jan;102:105-113

Isberg V, Andersen KB, Bisig C, Dietz GPH, Bräuner-Osborne H and Gloriam DE
Computer-aided Discovery of Aromatic L-α-amino acids as agonists of the orphan G protein-coupled receptor GPR139
J Chem Inf Model.  2014 May 14.; PMID: 24826842  

Identification of orphan receptor tool compounds
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.
Sci Rep. 2016 Nov 10;6:36681

Johansson H, Worch Boesgaard M, Nørskov-Lauritsen L, Larsen I, Kuhne S, and #Gloriam DE, #Bräuner-Osborne H , #Sejer Pedersen D
Selective allosteric antagonists for the G protein-coupled receptor GPRC6A based on the 2-phenylindole privileged structure scaffold
J. Med Chem, 2015 Nov 16.

Shehata MA, Belcik Christensen H, Isberg V, Pedersen D, Bender A, #Bräuner-Osborne H, #Gloriam DE.
Identification of the first surrogate agonists for the G protein-coupled receptor GPR132.
RSC Advances (IF 3.8), 2015; May 12 (5):48551-48557

Gloriam DE, Wellendorph P, Johansen LD, Thomsen AR, Phonekeo K, Pedersen DS, Bräuner-Osborne H
Chemogenomic Discovery of Novel Allosteric Antagonists at the GPRC6A Receptor
Chem Biol.  2011 Nov 23;18(11):1489-98; PMID: 22118683 

Identification of human orphan receptor genes
Gloriam DE, Schioth HB, Fredriksson R
Nine new human Rhodopsin family G-protein coupled receptors: identification, sequence characterisation and evolutionary relationships
Biochim Biophys Acta. 2005 Apr 15;1722(3):235-46.; PMID: 15777626 

Bjarnadottir TK, Fredriksson R, Hoglund PJ, Gloriam DE, Lagerstrom MC, Schioth HB
The human and mouse repertoire of the adhesion family of G-protein-coupled receptors
Genomics. 2004 Jul;84(1):23-33.; PMID: 15203201

Fredriksson R, Hoglund PJ, Gloriam DE, Lagerstrom MC, Schioth HB
Seven evolutionarily conserved human rhodopsin G protein-coupled receptors lacking close relatives
FEBS Lett. 2003 Nov 20;554(3):381-8.; PMID: 14623098 

Fredriksson R, Gloriam DE, Hoglund PJ, Lagerstrom MC, Schioth HB
There exist at least 30 human G-protein-coupled receptors with long Ser/Thr-rich N-termini
Biochem Biophys Res Commun. 2003 Feb 14;301(3):725-34.; PMID: 12565841