A biased ligand for OXE-R uncouples Gα and Gβγ signaling within a heterotrimer
The first small-molecule inhibitor of chemoattractant GPCR OXE-R disrupts signaling downstream of Gβγ but not Gα i/o , providing evidence that signaling bias can occur between Gβγ and Gα subunits within a heterotrimer. Differential targeting of heterotrimeric G protein versus β-arrestin signaling ar...
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| Veröffentlicht in: | Nature chemical biology 2012-07, Vol.8 (7), p.631-638 |
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| creator | Blättermann, Stefanie Peters, Lucas Ottersbach, Philipp Aaron Bock, Andreas Konya, Viktoria Weaver, C David Gonzalez, Angel Schröder, Ralf Tyagi, Rahul Luschnig, Petra Gäb, Jürgen Hennen, Stephanie Ulven, Trond Pardo, Leonardo Mohr, Klaus Gütschow, Michael Heinemann, Akos Kostenis, Evi |
| description | The first small-molecule inhibitor of chemoattractant GPCR OXE-R disrupts signaling downstream of Gβγ but not Gα
i/o
, providing evidence that signaling bias can occur between Gβγ and Gα subunits within a heterotrimer.
Differential targeting of heterotrimeric G protein versus β-arrestin signaling are emerging concepts in G protein–coupled receptor (GPCR) research and drug discovery, and biased engagement by GPCR ligands of either β-arrestin or G protein pathways has been disclosed. Herein we report on a new mechanism of ligand bias to titrate the signaling specificity of a cell-surface GPCR. Using a combination of biomolecular and virtual screening, we identified the small-molecule modulator Gue1654, which inhibits Gβγ but not Gα signaling triggered upon activation of Gα
i
-βγ by the chemoattractant receptor OXE-R in both recombinant and human primary cells. Gue1654 does not interfere nonspecifically with signaling directly at or downstream of Gβγ. This hitherto unappreciated mechanism of ligand bias at a GPCR highlights both a new paradigm for functional selectivity and a potentially new strategy to develop pathway-specific therapeutics. |
| doi_str_mv | 10.1038/nchembio.962 |
| format | Article |
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i/o
, providing evidence that signaling bias can occur between Gβγ and Gα subunits within a heterotrimer.
Differential targeting of heterotrimeric G protein versus β-arrestin signaling are emerging concepts in G protein–coupled receptor (GPCR) research and drug discovery, and biased engagement by GPCR ligands of either β-arrestin or G protein pathways has been disclosed. Herein we report on a new mechanism of ligand bias to titrate the signaling specificity of a cell-surface GPCR. Using a combination of biomolecular and virtual screening, we identified the small-molecule modulator Gue1654, which inhibits Gβγ but not Gα signaling triggered upon activation of Gα
i
-βγ by the chemoattractant receptor OXE-R in both recombinant and human primary cells. Gue1654 does not interfere nonspecifically with signaling directly at or downstream of Gβγ. This hitherto unappreciated mechanism of ligand bias at a GPCR highlights both a new paradigm for functional selectivity and a potentially new strategy to develop pathway-specific therapeutics.</description><identifier>ISSN: 1552-4450</identifier><identifier>EISSN: 1552-4469</identifier><identifier>DOI: 10.1038/nchembio.962</identifier><identifier>PMID: 22634634</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>631/154/436/2387 ; 631/80/86 ; 631/92/609 ; 631/92/613 ; Benzeneacetamides - metabolism ; Benzothiazoles - metabolism ; Biochemical Engineering ; Biochemistry ; Bioorganic Chemistry ; Biopolymers - metabolism ; Calcium - metabolism ; Cell Biology ; Cell Line ; Chemistry ; Chemistry and Materials Science ; Chemistry/Food Science ; Cyclic AMP - metabolism ; GTP-Binding Proteins - metabolism ; Humans ; Ligands ; Receptors, G-Protein-Coupled - metabolism ; Signal Transduction</subject><ispartof>Nature chemical biology, 2012-07, Vol.8 (7), p.631-638</ispartof><rights>Springer Nature America, Inc. 2012</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c329t-97a06b64f81584f49a4023fc03ef66da162a6c48ba54049cb9d55d554ee52b4a3</citedby><cites>FETCH-LOGICAL-c329t-97a06b64f81584f49a4023fc03ef66da162a6c48ba54049cb9d55d554ee52b4a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,27929,27930</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22634634$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Blättermann, Stefanie</creatorcontrib><creatorcontrib>Peters, Lucas</creatorcontrib><creatorcontrib>Ottersbach, Philipp Aaron</creatorcontrib><creatorcontrib>Bock, Andreas</creatorcontrib><creatorcontrib>Konya, Viktoria</creatorcontrib><creatorcontrib>Weaver, C David</creatorcontrib><creatorcontrib>Gonzalez, Angel</creatorcontrib><creatorcontrib>Schröder, Ralf</creatorcontrib><creatorcontrib>Tyagi, Rahul</creatorcontrib><creatorcontrib>Luschnig, Petra</creatorcontrib><creatorcontrib>Gäb, Jürgen</creatorcontrib><creatorcontrib>Hennen, Stephanie</creatorcontrib><creatorcontrib>Ulven, Trond</creatorcontrib><creatorcontrib>Pardo, Leonardo</creatorcontrib><creatorcontrib>Mohr, Klaus</creatorcontrib><creatorcontrib>Gütschow, Michael</creatorcontrib><creatorcontrib>Heinemann, Akos</creatorcontrib><creatorcontrib>Kostenis, Evi</creatorcontrib><title>A biased ligand for OXE-R uncouples Gα and Gβγ signaling within a heterotrimer</title><title>Nature chemical biology</title><addtitle>Nat Chem Biol</addtitle><addtitle>Nat Chem Biol</addtitle><description>The first small-molecule inhibitor of chemoattractant GPCR OXE-R disrupts signaling downstream of Gβγ but not Gα
i/o
, providing evidence that signaling bias can occur between Gβγ and Gα subunits within a heterotrimer.
Differential targeting of heterotrimeric G protein versus β-arrestin signaling are emerging concepts in G protein–coupled receptor (GPCR) research and drug discovery, and biased engagement by GPCR ligands of either β-arrestin or G protein pathways has been disclosed. Herein we report on a new mechanism of ligand bias to titrate the signaling specificity of a cell-surface GPCR. Using a combination of biomolecular and virtual screening, we identified the small-molecule modulator Gue1654, which inhibits Gβγ but not Gα signaling triggered upon activation of Gα
i
-βγ by the chemoattractant receptor OXE-R in both recombinant and human primary cells. Gue1654 does not interfere nonspecifically with signaling directly at or downstream of Gβγ. This hitherto unappreciated mechanism of ligand bias at a GPCR highlights both a new paradigm for functional selectivity and a potentially new strategy to develop pathway-specific therapeutics.</description><subject>631/154/436/2387</subject><subject>631/80/86</subject><subject>631/92/609</subject><subject>631/92/613</subject><subject>Benzeneacetamides - metabolism</subject><subject>Benzothiazoles - metabolism</subject><subject>Biochemical Engineering</subject><subject>Biochemistry</subject><subject>Bioorganic Chemistry</subject><subject>Biopolymers - metabolism</subject><subject>Calcium - metabolism</subject><subject>Cell Biology</subject><subject>Cell Line</subject><subject>Chemistry</subject><subject>Chemistry and Materials Science</subject><subject>Chemistry/Food Science</subject><subject>Cyclic AMP - metabolism</subject><subject>GTP-Binding Proteins - metabolism</subject><subject>Humans</subject><subject>Ligands</subject><subject>Receptors, G-Protein-Coupled - metabolism</subject><subject>Signal Transduction</subject><issn>1552-4450</issn><issn>1552-4469</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkF1LwzAUhoMobk7vvJZcemFnmq81l2PMKQyGouBdSdu0y2iTmbSIP0v9H_tNZuzjSjhwDrwPL4cHgOsYDWNEknuTL1WTaTsUHJ-AfswYjijl4vR4M9QDF96vECKcx8k56GHMCQ3TB89jmGnpVQFrXUlTwNI6uHifRi-wM7nt1rXycLb5httstvnZ_EKvKyNrbSr4qdulNlDCpWqVs63TjXKX4KyUtVdX-z0Abw_T18ljNF_MnibjeZQTLNpIjCTiGadlErOEllRIijApc0RUyXkhY44lz2mSSUYRFXkmCsbCUKUYzqgkA3C76107-9Ep36aN9rmqa2mU7Xwa5LAYjQQlAb3bobmz3jtVpuvwqnRfAdpySXqQmAaJAb_ZN3dZo4ojfLAWgGgH-BCZSrl0ZTsXpPj_C_8AbQh_jw</recordid><startdate>20120701</startdate><enddate>20120701</enddate><creator>Blättermann, Stefanie</creator><creator>Peters, Lucas</creator><creator>Ottersbach, Philipp Aaron</creator><creator>Bock, Andreas</creator><creator>Konya, Viktoria</creator><creator>Weaver, C David</creator><creator>Gonzalez, Angel</creator><creator>Schröder, Ralf</creator><creator>Tyagi, Rahul</creator><creator>Luschnig, Petra</creator><creator>Gäb, Jürgen</creator><creator>Hennen, Stephanie</creator><creator>Ulven, Trond</creator><creator>Pardo, Leonardo</creator><creator>Mohr, Klaus</creator><creator>Gütschow, Michael</creator><creator>Heinemann, Akos</creator><creator>Kostenis, Evi</creator><general>Nature Publishing Group US</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20120701</creationdate><title>A biased ligand for OXE-R uncouples Gα and Gβγ signaling within a heterotrimer</title><author>Blättermann, Stefanie ; 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i/o
, providing evidence that signaling bias can occur between Gβγ and Gα subunits within a heterotrimer.
Differential targeting of heterotrimeric G protein versus β-arrestin signaling are emerging concepts in G protein–coupled receptor (GPCR) research and drug discovery, and biased engagement by GPCR ligands of either β-arrestin or G protein pathways has been disclosed. Herein we report on a new mechanism of ligand bias to titrate the signaling specificity of a cell-surface GPCR. Using a combination of biomolecular and virtual screening, we identified the small-molecule modulator Gue1654, which inhibits Gβγ but not Gα signaling triggered upon activation of Gα
i
-βγ by the chemoattractant receptor OXE-R in both recombinant and human primary cells. Gue1654 does not interfere nonspecifically with signaling directly at or downstream of Gβγ. This hitherto unappreciated mechanism of ligand bias at a GPCR highlights both a new paradigm for functional selectivity and a potentially new strategy to develop pathway-specific therapeutics.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>22634634</pmid><doi>10.1038/nchembio.962</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1552-4450 |
| ispartof | Nature chemical biology, 2012-07, Vol.8 (7), p.631-638 |
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| language | eng |
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| source | MEDLINE; Nature; Alma/SFX Local Collection |
| subjects | 631/154/436/2387 631/80/86 631/92/609 631/92/613 Benzeneacetamides - metabolism Benzothiazoles - metabolism Biochemical Engineering Biochemistry Bioorganic Chemistry Biopolymers - metabolism Calcium - metabolism Cell Biology Cell Line Chemistry Chemistry and Materials Science Chemistry/Food Science Cyclic AMP - metabolism GTP-Binding Proteins - metabolism Humans Ligands Receptors, G-Protein-Coupled - metabolism Signal Transduction |
| title | A biased ligand for OXE-R uncouples Gα and Gβγ signaling within a heterotrimer |
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