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Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65

Xi-Ping Huang, Joel Karpiak, Wesley K. Kroeze, Hu Zhu, Xin Chen, Sheryl S. Moy, Kara A. Saddoris, Viktoriya D. Nikolova, Martilias S. Farrell, Sheng Wang, Thomas J. Mangano, Deepak A. Deshpande (+7 others)
2015 Nature  
The same approach led to the discovery of allosteric agonists and negative allosteric modulators for GPR65.  ...  -P.H. subcloned GPR68 for yeast screening, made GPR68 and GPR65 mutants, designed, carried out cell-based screening assays, analyzed results, and wrote the paper. J.  ...  Acknowledgments . ) for providing us G s -and G q -yeast strains for yeast screening assays.  ... 
doi:10.1038/nature15699 pmid:26550826 pmcid:PMC4796946 fatcat:75xzcv52ifcorfv3frfvbukr6e

DCyFIR: a high-throughput CRISPR platform for multiplexed G protein-coupled receptor profiling and ligand discovery [article]

Nicholas J Kapolka, Geoffrey J Taghon, Jacob B Rowe, William M Morgan, Jay F Enten, Daniel G Isom
2020 bioRxiv   pre-print
Remarkably, many of these findings pertained to understudied, pharmacologically dark receptors GPR4, GPR65, GPR68, and HCAR3.  ...  Taken together, these findings demonstrate the power of DCyFIR for identifying novel ligand interactions with prototypic and understudied GPCRs.  ...  This work was supported by the NIH through the NIGMS (R35GM119518) and NIH Common Fund for Illuminating the Druggable Genome (R03TR002908) to D.G.I.  ... 
doi:10.1101/2020.01.16.909325 fatcat:koi5bvwlebbyroythqef4jajgy

Recent Trends and Applications of Molecular Modeling in GPCR–Ligand Recognition and Structure-Based Drug Design

Xiaojing Yuan, Yechun Xu
2018 International Journal of Molecular Sciences  
G protein-coupled receptors represent the largest family of human membrane proteins and are modulated by a variety of drugs and endogenous ligands.  ...  Notably, the crucial role of the membrane in the ligand-receptor association process has earned much attention.  ...  Recently, SBDD has been combined with physical screening to demystify two pharmacologically dark GPCRs, GPR68 and GPR65 [104] .  ... 
doi:10.3390/ijms19072105 pmid:30036949 pmcid:PMC6073596 fatcat:4n5qxfikzvd27i7nl7acsdhx6u

Discovery of Human Signaling Systems: Pairing Peptides to G Protein-Coupled Receptors

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 (+1 others)
2019 Cell  
We also identify additional peptides for nine receptors with recognized ligands and pathophysiological roles.  ...  However, the physiological roles remain elusive for numerous peptides and more than 100 G protein-coupled receptors (GPCRs). Here we report the pairing of cognate peptides and receptors.  ...  Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65. Nature 527, 477-483. Ignatov, A., Hermans-Borgmeyer, I., and Schaller, H.C. (2004).  ... 
doi:10.1016/j.cell.2019.10.010 pmid:31675498 pmcid:PMC6838683 fatcat:usfzdv75rvc55pqiyh65ikq44a

The Impact of the Secondary Binding Pocket on the Pharmacology of Class A GPCRs

Attila Egyed, Dóra Judit Kiss, György M. Keserű
2022 Frontiers in Pharmacology  
In some cases, it serves as a stable allosteric site harbouring allosteric ligands that modulate the pharmacology of orthosteric binders.  ...  In other cases it is used by bitopic compounds occupying both the OBP and SBP. In these terms, SBP binding moieties might influence the pharmacology of the bitopic ligands.  ...  Huang et al. developed a protocol combining homology modelling and docking to find novel allosteric modulators of the orphan GPR68 and GPR65 receptors (Huang et al., 2015) .  ... 
doi:10.3389/fphar.2022.847788 pmid:35355719 pmcid:PMC8959758 fatcat:qf47wiszrvakloixhaqj2p4kcu

Docking Screens for Novel Ligands Conferring New Biology

John J. Irwin, Brian K. Shoichet
2016 Journal of Medicinal Chemistry  
Recent docking screens for new ligands are sketched, as are the binding, crystallographic, and in vivo assays that support them.  ...  Here we summarize the improvements in libraries, target quality, and methods that have supported these advances, and the open access resources that make docking accessible.  ...  We thank Trent Balius, Marcus Fischer, and Matt O'Meara for reading the manuscript.  ... 
doi:10.1021/acs.jmedchem.5b02008 pmid:26913380 pmcid:PMC4865415 fatcat:f5b6zfdmrfd3fe5x5khlbsau5e

Application of GPCR Structures for Modelling of Free Fatty Acid Receptors [chapter]

Irina G. Tikhonova
2016 Handbook of Experimental Pharmacology  
, distinct structural features for ligand binding to FFA1 and FFA4 and an arginine of the second extracellular loop as a possible anchoring point for FFA at GPR84.  ...  Free fatty acid receptors have now emerged as potential targets for the treatment of diabetes, obesity and immune diseases.  ...  In the recent study Huang and colleagues have used homology models of the poor-characterized receptors, GPR68 and GPR65 for virtual screening and identified potent ligands (Huang et al. 2015) .  ... 
doi:10.1007/164_2016_52 pmid:27757764 fatcat:2vno7b6omfbobjdq2vdifqsb74

Class A Orphans in GtoPdb v.2021.3

Stephen P.H. Alexander, Jim Battey, Helen E. Benson, Richard V. Benya, Tom I. Bonner, Anthony P. Davenport, Khuraijam Dhanachandra Singh, Satoru Eguchi, Anthony Harmar, Nick Holliday, Robert T. Jensen, Sadashiva Karnik (+15 others)
2021 IUPHAR/BPS Guide to Pharmacology CITE  
GPR22GPR26GPR31GPR34GPR35GPR37GPR39 GPR50GPR63GRP65GPR68GPR75GPR84GPR87 GPR88GPR132GPR149GPR161GPR183LGR4LGR5 LGR6MAS1MRGPRDMRGPRX1MRGPRX2P2RY10TAAR2 In addition the orphan receptors GPR18, GPR55 and  ...  GPR119 which are reported to respond to endogenous agents analogous to the endogenous cannabinoid ligands have been grouped together (GPR18, GPR55 and GPR119).  ...  Huang XP, Karpiak J, Kroeze WK, Zhu H, Chen X, Moy SS, Saddoris KA, Nikolova VD, Farrell MS and Wang S et al.. (2015) Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65.  ... 
doi:10.2218/gtopdb/f16/2021.3 fatcat:vezw2mxcqzbfdg2dmfcjjwnyzu

Class A Orphans (version 2020.5) in the IUPHAR/BPS Guide to Pharmacology Database

Stephen P.H. Alexander, Jim Battey, Helen E. Benson, Richard V. Benya, Tom I. Bonner, Anthony P. Davenport, Khuraijam Dhanachandra Singh, Satoru Eguchi, Anthony Harmar, Nick Holliday, Robert T. Jensen, Sadashiva Karnik (+15 others)
2020 IUPHAR/BPS Guide to Pharmacology CITE  
receptors GPR18, GPR55 and GPR119 which are reported to respond to endogenous agents analogous to the endogenous cannabinoid ligands have been grouped together (GPR18, GPR55 and GPR119).  ...  Table 1 lists a number of putative GPCRs identified by NC-IUPHAR [194], for which preliminary evidence for an endogenous ligand has been published, or for which there exists a potential link to a disease  ...  Huang XP, Karpiak J, Kroeze WK, Zhu H, Chen X, Moy SS, Saddoris KA, Nikolova VD, Farrell MS and Wang S et al.. (2015) Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65.  ... 
doi:10.2218/gtopdb/f16/2020.5 fatcat:gg6vvpnn3ncxriaawrcup3w4eq

SARS-CoV-2 proteins (version 2020.2) in the IUPHAR/BPS Guide to Pharmacology Database

Stephen P.H. Alexander, Jonathan K. Ball, Theocharis Tsoleridis
2020 IUPHAR/BPS Guide to Pharmacology CITE  
The remainder of the genome encodes elements for viral replication, assembly and release, as well as proteins which manipulate the host's innate immune system.  ...  This binding facilitates viral entry into the cell and the release of the genome.  ...  Huang XP, Karpiak J, Kroeze WK, Zhu H, Chen X, Moy SS, Saddoris KA, Nikolova VD, Farrell MS and Wang S et al.. (2015) Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65.  ... 
doi:10.2218/gtopdb/f16/2019.5 fatcat:ec34rxyfmvamvg6qgtgcoov54u

Guide to Receptors and Channels (GRAC), 5th edition

SPH Alexander, A Mathie, JA Peters
2011 British Journal of Pharmacology  
Molecular cloning and characterisation of avian bombesin-like peptide receptors: new tools for investigating molecular basis of ligand selectivity. Br J Pharmacol 139: 555-566.  ...  International Union of Pharmacology. LXVIII. Mammalian bombesin receptors: nomenclature, distribution, pharmacology, signaling and function in normal and disease states. Pharmacol Rev 60: 1-42.  ...  Marked species differences in pharmacology exist for all three receptors, in particular with nonpeptide ligands.  ... 
doi:10.1111/j.1476-5381.2011.01649_1.x pmid:22040146 pmcid:PMC3315626 fatcat:x5mqndw6ibf4zat44w3tpg2ywq

Consultants

SPH Alexander, A Mathie, JA Peters
2011 British Journal of Pharmacology  
Molecular cloning and characterisation of avian bombesin-like peptide receptors: new tools for investigating molecular basis of ligand selectivity. Br J Pharmacol 139: 555-566.  ...  International Union of Pharmacology. LXVIII. Mammalian bombesin receptors: nomenclature, distribution, pharmacology, signaling and function in normal and disease states. Pharmacol Rev 60: 1-42.  ...  Marked species differences in pharmacology exist for all three receptors, in particular with nonpeptide ligands.  ... 
doi:10.1111/j.1476-5381.2011.01649_2.x fatcat:y7cie5yekzhvlhhlxxbiaymlia

Class A Orphans (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Stephen P.H. Alexander, Jim Battey, Helen E. Benson, Richard V. Benya, Tom I. Bonner, Anthony P. Davenport, Satoru Eguchi, Anthony Harmar, Nick Holliday, Robert T. Jensen, Sadashiva Karnik, Evi Kostenis (+14 others)
2019 IUPHAR/BPS Guide to Pharmacology CITE  
GPR22GPR26GPR31GPR34GPR35GPR37GPR39 GPR50GPR63GRP65GPR68GPR75GPR84GPR87 GPR88GPR132GPR149GPR161GPR183LGR4LGR5 LGR6MAS1MRGPRDMRGPRX1MRGPRX2P2RY10TAAR2 In addition the orphan receptors GPR18, GPR55 and  ...  GPR119 which are reported to respond to endogenous agents analogous to the endogenous cannabinoid ligands have been grouped together (GPR18, GPR55 and GPR119).  ...  Huang XP, Karpiak J, Kroeze WK, Zhu H, Chen X, Moy SS, Saddoris KA, Nikolova VD, Farrell MS and Wang S et al.. (2015) Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65.  ... 
doi:10.2218/gtopdb/f16/2019.4 fatcat:ecs5f7y56fayjiogxaivbno66q

Discovery of Human Signaling Systems: Pairing Peptides to G Protein-Coupled Receptors

D.E. Gloriam, A.S. Hauser, B.L. Roth, L.M. Haugaard-Kedström, S.R. Foster, L. Vedel, A.C. Gavin, R.B. Penn, R.T. Strachan, A.P. Nayak, H. Bräuner-Osborne, X.-P. Huang (+1 others)
2019
We also identify additional peptides for nine receptors with recognized ligands and pathophysiological roles.  ...  However, the physiological roles remain elusive for numerous peptides and more than 100 G protein-coupled receptors (GPCRs). Here we report the pairing of cognate peptides and receptors.  ...  Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65. Nature 527, 477-483. Ignatov, A., Hermans-Borgmeyer, I., and Schaller, H.C. (2004).  ... 
doi:10.17615/9xfr-er83 fatcat:oom6zoo3znfm5opelpxiimqayq

CNS distribution, signalling properties and central effects of G-protein coupled receptor 4

P.S. Hosford, V. Mosienko, K. Kishi, G. Jurisic, K. Seuwen, B. Kinzel, M.G. Ludwig, J.A. Wells, I.N. Christie, L. Koolen, A.P. Abdala, B.H. Liu (+3 others)
2018 Neuropharmacology  
Information on the distribution and biology of the G-protein coupled receptor 4 (GPR4) in the brain is limited.  ...  The main extracellular organic acid, L-lactic acid (LL; 1e10 mM), suppressed pH dependent activation of GPR4 in HEK293 and HUVEC cells, suggesting allosteric negative modulation.  ...  Conflicts of interest The authors declare no conflict of interest. Appendix A.  ... 
doi:10.1016/j.neuropharm.2018.06.007 pmid:29894771 pmcid:PMC6063991 fatcat:lxcjh4nb7naflagnsk7aoqgnxa