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      PRESTO-TANGO: an open-source resource for interrogation of the druggable human GPCR-ome

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          Abstract

          G protein-coupled receptors (GPCRs) are essential mediators of cellular signaling and important targets of drug action. Of the approximately 350 non-olfactory human GPCRs, more than 100 are still considered “orphans” as their endogenous ligand(s) remain unknown. Here, we describe a unique open-source resource that provides the capacity to interrogate the druggable human GPCR-ome via a G protein-independent β-arrestin recruitment assay. We validate this unique platform at more than 120 non-orphan human GPCR targets, demonstrate its utility for discovering new ligands for orphan human GPCRs, and describe a method ( PRESTO-TANGO; Parallel Receptor-ome Expression and Screening via Transcriptional Output - TANGO) for the simultaneous and parallel interrogation of the entire human GPCR-ome.

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          Transduction of receptor signals by beta-arrestins.

          Robert Lefkowitz, Sudha Shenoy (2005)
          The transmission of extracellular signals to the interior of the cell is a function of plasma membrane receptors, of which the seven transmembrane receptor family is by far the largest and most versatile. Classically, these receptors stimulate heterotrimeric G proteins, which control rates of generation of diffusible second messengers and entry of ions at the plasma membrane. Recent evidence, however, indicates another previously unappreciated strategy used by the receptors to regulate intracellular signaling pathways. They direct the recruitment, activation, and scaffolding of cytoplasmic signaling complexes via two multifunctional adaptor and transducer molecules, beta-arrestins 1 and 2. This mechanism regulates aspects of cell motility, chemotaxis, apoptosis, and likely other cellular functions through a rapidly expanding list of signaling pathways.
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            Structural features for functional selectivity at serotonin receptors.

            Daniel Wacker, Chong Wang, Vsevolod Katritch … (2013)
            Drugs active at G protein-coupled receptors (GPCRs) can differentially modulate either canonical or noncanonical signaling pathways via a phenomenon known as functional selectivity or biased signaling. We report biochemical studies showing that the hallucinogen lysergic acid diethylamide, its precursor ergotamine (ERG), and related ergolines display strong functional selectivity for β-arrestin signaling at the 5-HT2B 5-hydroxytryptamine (5-HT) receptor, whereas they are relatively unbiased at the 5-HT1B receptor. To investigate the structural basis for biased signaling, we determined the crystal structure of the human 5-HT2B receptor bound to ERG and compared it with the 5-HT1B/ERG structure. Given the relatively poor understanding of GPCR structure and function to date, insight into different GPCR signaling pathways is important to better understand both adverse and favorable therapeutic activities.
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              Structure of the human kappa opioid receptor in complex with JDTic

              Huixian Wu, Daniel Wacker, Vsevolod Katritch … (2012)
              Opioid receptors (ORs) mediate the actions of endogenous and exogenous opioids for many essential physiological processes including regulation of pain, respiratory drive, mood, and, in the case of κ-opioid receptors (KOR), dysphoria and psychotomimesis. Here we report the crystal structure of the human KOR (hKOR) in complex with the selective antagonist JDTic, arranged in parallel-dimers, at 2.9 angstrom resolution. The structure reveals important features of the ligand binding pocket that contribute to JDTic’s high affinity and subtype-selectivity for hKOR. Modeling of other important KOR-selective ligands, including the morphinan-derived antagonists nor-BNI and GNTI, and the diterpene agonist salvinorin A analog RB-64, reveals both common and distinct features for binding these diverse chemotypes. Analysis of site-directed mutagenesis and ligand structure-activity relationships confirms the interactions observed in the crystal structure, thereby providing a molecular explanation for hKOR subtype-selectivity along with insight essential for the design of hKOR compounds with new pharmacological properties.
              Article 0 comments Cited 202 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 101186374
                Journal ID (pubmed-jr-id): 31761
                Journal ID (nlm-ta): Nat Struct Mol Biol
                Journal ID (iso-abbrev): Nat. Struct. Mol. Biol.
                Title: Nature structural & molecular biology
                ISSN (Print): 1545-9993
                ISSN (Electronic): 1545-9985
                Publication date Nihms-submitted: 28 March 2015
                Publication date (Electronic): 20 April 2015
                Publication date (Print): May 2015
                Publication date PMC-release: 01 November 2015
                Volume: 22
                Issue: 5
                Pages: 362-369
                Affiliations
                [1 ]Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27514, and National Institute of Mental Health Psychoactive Drug Screening Program 1, University of North Carolina, Chapel Hill, NC 27514
                [2 ]Program in Neuroscience, University of North Carolina, Chapel Hill, NC 27514, and Division of Chemical Biology and Medicinal Chemistry 2, University of North Carolina, Chapel Hill, NC 27514
                Author notes
                Corresponding author: Bryan L. Roth, 4072 Genetic Medicine, UNC-CH School of Medicine, Chapel Hill, NC 27599-7365; Phone: 919-966-7535; Fax: 919-843-5788; bryan_roth@ 123456med.unc.edu

                WKK, MFS and X-P H: Contributed equally

                Article
                Manuscript ID: NIHMS675684
                DOI: 10.1038/nsmb.3014
                PMC ID: 4424118
                PubMed ID: 25895059
                SO-VID: bc5f2071-d431-4e0b-b78f-08cbd9949c7b
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                ScienceOpen disciplines: Molecular biology
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                ScienceOpen disciplines: Molecular biology

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