ORCID Profile
0000-0003-0670-6648
Current Organisation
Fujifilm Diosynth Biotechnologies
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Publisher: Cold Spring Harbor Laboratory
Date: 14-08-2019
DOI: 10.1101/730622
Abstract: The human M 5 muscarinic acetylcholine receptor (mAChR) has recently emerged as an exciting therapeutic target for treating a range of disorders, including drug addiction. However, a lack of structural information for this receptor subtype has limited further drug development and validation. Here we report a high-resolution crystal structure of the human M 5 mAChR bound to the clinically used inverse agonist, tiotropium. This structure allowed for a comparison across all five mAChR family members that revealed important differences in both orthosteric and allosteric sites that could inform the rational design of selective ligands. These structural studies together with chimeric swaps between the extracellular regions of the M 2 and M 5 mAChR further revealed the structural insight into “kinetic-selectivity”, where ligands show differential residency times between related family members. Collectively, our study provides important insights into the nature of orthosteric and allosteric ligand interaction across the mAChR family that could be exploited for the design of selective ligands. The five subtypes of the muscarinic acetylcholine receptors (mAChRs) are expressed throughout the central and peripheral nervous system where they play a vital role in physiology and pathologies. Recently, the M 5 mAChR subtype has emerged as an exciting drug target for the treatment of drug addiction. We have determined the atomic structure of the M 5 mAChR bound to the clinically used inverse agonist tiotropium. The M 5 mAChR structure now allows for a full comparison of all five mAChR subtypes and reveals subtle differences in the extracellular loop (ECL) regions of the receptor that mediate orthosteric and allosteric ligand selectivity. Together these findings open the door for future structure-based design of selective drugs that target this therapeutically important class of receptors.
Publisher: Wiley
Date: 06-2022
DOI: 10.1111/BCPT.13738
Abstract: The GPR15 receptor is a G protein‐coupled receptor (GPCR), which is activated by an endogenous peptide GPR15L(25–81) and a C‐terminal peptide fragment GPR15L(71–81). GPR15 signals through the G i/o pathway to decrease intracellular cyclic adenosine 3′,5′‐monophosphate (cAMP). However, the activation profiles of the GPR15 receptor within G i/o subtypes have not been examined. Moreover, whether the receptor can also couple to G s , G q/11 and G 12/13 is unclear. Here, GPR15L(25–81) and GPR15L(71–81) are used as pharmacological tool compounds to delineate the GPR15 receptor‐mediated Gα protein signalling using a G protein activation assay and second messenger assay conducted on living cells. The results show that the GPR15 receptor preferentially couples to G i/o rather than other pathways in both assays. Within the G i/o family, the GPR15 receptor activates all the subtypes (G i1 , G i2 , G i3 , G oA , G oB and G z ). The E max and activation rates of G i1, G i2 , G i3, G oA and G oB are similar, whilst the E max of G z is smaller and the activation rate is significantly slower. The potencies of both peptides toward each G i/o subtype have been determined. Furthermore, the GPR15 receptor signals through G i/o to inhibit cAMP accumulation, which could be blocked by the application of the G i/o inhibitor pertussis toxin.
Publisher: Springer Science and Business Media LLC
Date: 07-03-2019
DOI: 10.1038/S41598-019-40085-9
Abstract: GPR139 is an orphan G protein-coupled receptor (GPCR) that is primarily expressed in the brain in regions known to regulate motor control and metabolism. Here, we screened a erse 4,000 compound library in order to identify GPR139 agonists. We identified 11 initial hits in a calcium mobilization screen, including one compound, AC4, which contains a different chemical scaffold to what has previously been described for GPR139 agonists. Our mutagenesis data shows that AC4 interacts with the same hotspots in the binding site of GPR139 as those reported to interact with the reference agonists 1a and 7c. We additionally tested and validated 160 analogs in a calcium mobilization assay and found 5 compounds with improved potency compared to AC4. In total, we identified 36 GPR139 agonists with potencies in the nanomolar range (90–990 nM). The most potent compounds were confirmed as GPR139 agonists using an orthogonal ERK phosphorylation assay where they displayed a similar rank order of potency. Accordingly, we herein introduce multiple novel GPR139 agonists, including one with a novel chemical scaffold, which can be used as tools for future pharmacological and medicinal chemistry exploration of GPR139.
Location: United States of America
Start Date: 2015
End Date: 2016
Funder: American Australian Association
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