Structure-activity relationships of agonists for the orphan G protein-coupled receptor GPR27

Pillaiyar, Thanigaimalai; Rosato, Francesca; Woźniak, Monika; Blavier, Jeremy; Charles, Maëlle; Laschet, Céline; Kronenberger, Thales; Müller, Christa E.; Hanson, Julien

doi:10.1016/j.ejmech.2021.113777

Cited by 13 publications

(14 citation statements)

References 30 publications

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“…Notably, a previous study reported that ADGRD1 was agonized by binding to its N-terminal stalk 51 . 25-hydroxycholesterol displayed the strongest GPCR-ML score for GPR27, with binding to an extracellular site that is different from the reported binding site 32 .…”

Section: Resultscontrasting

confidence: 66%

“…Three of the GPCRs identified in this exercise are also orphan GPCRs: GPR27, adhesion receptor ADGRD1, and photoreceptor OPN4. Expression of ADGRD1 has been reported in immune cells, and GPR27 is specifically expressed in the brain and is involved in neuronal plasticity and cognition [32][33][34] . For reference, the AlphaFold2 structural models of GPR27 and ADGRD1 are shown in Fig.…”

Section: Multi-omics Analysis Reveals Potential Gpcr Targets For Alzh...mentioning

confidence: 99%

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Comprehensive characterization of multi-omic landscapes between gut-microbiota metabolites and the G-protein-coupled receptors in Alzheimer’s disease

Qiu

Hou

Zhou

et al. 2022

Preprint

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Accumulating evidence suggests that gut-microbiota metabolites contribute to human disease pathophysiology, yet the host receptors that sense these metabolites are largely unknown. Here, we developed a systems pharmacogenomics framework that integrates machine learning (ML), AlphaFold2-derived structural pharmacology, and multi-omics to identify disease-relevant metabolites derived from gut-microbiota with non-olfactory G-protein-coupled receptors (GPCRome). Specifically, we evaluated 1.68 million metabolite-protein pairs connecting 408 human GPCRs and 516 gut metabolites using an Extra Trees algorithm-improved structural pharmacology strategy. Using genetics-derived Mendelian randomization and multi-omics (including transcriptomic and proteomic) analyses, we identified likely causal GPCR targets (C3AR, FPR1, GALR1 and TAS2R60) in Alzheimer's disease (AD). Using three-dimensional structural fingerprint analysis of the metabolite-GPCR complexome, we identified over 60% of the allosteric pockets of orphan GPCR models for gut metabolites in the GPCRome, including AD-related orphan GPCRs (GPR27, GPR34, and GPR84). We additionally identified the potential targets (e.g., C3AR) of two AD-related metabolites (3-hydroxybutyric acid and Indole-3-pyruvic acid) and four metabolites from AD-related bacterium Eubacterium rectale, and also showed that tridecylic acid is a candidate ligand for orphan GPR84 in AD. In summary, this study presents a systems pharmacogenomics approach that serves to uncover the GPCR molecular targets of gut microbiota in AD and likely many other human diseases if broadly applied.

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Section: Resultscontrasting

confidence: 66%

Section: Multi-omics Analysis Reveals Potential Gpcr Targets For Alzh...mentioning

confidence: 99%

Comprehensive characterization of multi-omic landscapes between gut-microbiota metabolites and the G-protein-coupled receptors in Alzheimer’s disease

Qiu

Hou

Zhou

et al. 2022

Preprint

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“…Among the deletions, we detected clustered small genomic deletions located in the GPR27 region of PD patients. GPR27 is a G protein-coupled receptor involved in neuronal plasticity and energy metabolism and is expressed in the brain 47 . In particular, the small deleted regions are enhancers located in the TAD, suggesting that their alterations may affect protein production, unlike other SNVs in noncoding regions.…”

Section: Discussionmentioning

confidence: 99%

Whole-genome sequencing reveals an association between small genomic deletions and an increased risk of developing Parkinson’s disease

Park

et al. 2023

Exp Mol Med

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Single-nucleotide variants (SNVs) associated with Parkinson’s disease (PD) have been investigated mainly through genome-wide association studies. However, other genomic alterations, including copy number variations, remain less explored. In this study, we conducted whole-genome sequencing of primary (310 PD patients and 100 healthy individuals) and independent (100 PD patients and 100 healthy individuals) cohorts from the Korean population to identify high-resolution small genomic deletions, gains, and SNVs. Global small genomic deletions and gains were found to be associated with an increased and decreased risk of PD development, respectively. Thirty significant locus deletions were identified in PD, with most being associated with an increased PD risk in both cohorts. Small genomic deletions in clustered loci located in the GPR27 region had high enhancer signals and showed the closest association with PD. GPR27 was found to be expressed specifically in brain tissue, and GPR27 copy number loss was associated with upregulated SNCA expression and downregulated dopamine neurotransmitter pathways. Clustering of small genomic deletions on chr20 in exon 1 of the GNAS isoform was detected. In addition, we found several PD-associated SNVs, including one in the enhancer region of the TCF7L2 intron, which exhibited a cis-acting regulatory mode and an association with the beta-catenin signaling pathway. These findings provide a global, whole-genome view of PD and suggest that small genomic deletions in regulatory domains contribute to the risk of PD development.

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“…Its sulfonamide group stably interacts with the Leu173's backbone (∼94%) and to some extent with Cys95 (∼25%), locking it on the surface of the pocket. Our previous work 18 suggested, based on a combination of docking and WaterMap studies, that the orthosteric pocket's bottom harbors high-energy hydration sites, which could contribute to the binding energy when occupied by hydrophobic moieties. Here, we establish the relevance of trisubstituted aryl rings, in comparison with the double substituted ones, in occupying this deeper pocket since the compounds with longer interaction time were also more active.…”

Section: Evaluation Of Compounds On Gpr27 Without the Vmentioning

confidence: 99%

Development of Ligands for the Super Conserved Orphan G Protein-Coupled Receptor GPR27 with Improved Efficacy and Potency

Pillaiyar,

Wozniak,

Abboud

et al. 2023

J. Med. Chem.

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Structure-activity relationships of agonists for the orphan G protein-coupled receptor GPR27

Cited by 13 publications

References 30 publications

Comprehensive characterization of multi-omic landscapes between gut-microbiota metabolites and the G-protein-coupled receptors in Alzheimer’s disease

Comprehensive characterization of multi-omic landscapes between gut-microbiota metabolites and the G-protein-coupled receptors in Alzheimer’s disease

Whole-genome sequencing reveals an association between small genomic deletions and an increased risk of developing Parkinson’s disease

Development of Ligands for the Super Conserved Orphan G Protein-Coupled Receptor GPR27 with Improved Efficacy and Potency

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