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A biased ligand for OXE-R uncouples Gα and Gβγ signaling within a heterotrimer

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Stefanie Blättermann
  • Lucas Peters
  • Philipp Aaron Ottersbach
  • Andreas Bock
  • Viktoria Konya
  • C David Weaver
  • Angel Gonzalez
  • Ralf Schröder
  • Rahul Tyagi
  • Petra Luschnig
  • Jürgen Gäb
  • Stephanie Hennen
  • Ulven, Trond
  • Leonardo Pardo
  • Klaus Mohr
  • Michael Gütschow
  • Akos Heinemann
  • Evi Kostenis
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.
OriginalsprogEngelsk
TidsskriftNature Chemical Biology
Vol/bind8
Udgave nummer7
Sider (fra-til)631-638
Antal sider8
ISSN1552-4450
DOI
StatusUdgivet - 2012

ID: 189162465