Discovery of small-molecule modulator of heterotrimeric Gi-protein by integrated phenotypic profiling and chemical proteomics

DOI PDF 研究データあり 参考文献32件
  • Tatsuro Kawamura
    RIKEN-Max Planck Joint Research Division for Systems Chemical Biology, RIKEN Center for Sustainable Resource Science, Saitama, Japan
  • Yushi Futamura
    Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, Saitama, Japan
  • Erchang Shang
    Max Planck Institute of Molecular Physiology, Department of Chemical Biology, Dortmund, Germany
  • Makoto Muroi
    RIKEN-Max Planck Joint Research Division for Systems Chemical Biology, RIKEN Center for Sustainable Resource Science, Saitama, Japan
  • Petra Janning
    Max Planck Institute of Molecular Physiology, Department of Chemical Biology, Dortmund, Germany
  • Masayoshi Ueno
    Faculty of Science and Technology, Division of Molecular Science, Gunma University, Kiryu, Gunma, Japan
  • Julian Wilke
    RIKEN-Max Planck Joint Research Division for Systems Chemical Biology, RIKEN Center for Sustainable Resource Science, Saitama, Japan
  • Shigeki Takeda
    Faculty of Science and Technology, Division of Molecular Science, Gunma University, Kiryu, Gunma, Japan
  • Yasumitsu Kondoh
    Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, Saitama, Japan
  • Slava Ziegler
    Max Planck Institute of Molecular Physiology, Department of Chemical Biology, Dortmund, Germany
  • Nobumoto Watanabe
    RIKEN-Max Planck Joint Research Division for Systems Chemical Biology, RIKEN Center for Sustainable Resource Science, Saitama, Japan
  • Herbert Waldmann
    Max Planck Institute of Molecular Physiology, Department of Chemical Biology, Dortmund, Germany
  • Hiroyuki Osada
    RIKEN-Max Planck Joint Research Division for Systems Chemical Biology, RIKEN Center for Sustainable Resource Science, Saitama, Japan

この論文をさがす

説明

<jats:title>Abstract</jats:title> <jats:p>Discovery of small-molecule inducers of unique phenotypic changes combined with subsequent target identification often provides new insights into cellular functions. Here, we applied integrated profiling based on cellular morphological and proteomic changes to compound screening. We identified an indane derivative, NPD9055, which is mechanistically distinct from reference compounds with known modes of action. Employing a chemical proteomics approach, we then showed that NPD9055 binds subunits of heterotrimeric G-protein Gi. An in vitro [35S]GTPγS-binding assay revealed that NPD9055 inhibited GDP/GTP exchange on a Gαi subunit induced by a G-protein-coupled receptor agonist, but not on another G-protein from the Gαs family. In intact HeLa cells, NPD9055 induced an increase in intracellular Ca2+ levels and ERK/MAPK phosphorylation, both of which are regulated by Gβγ, following its dissociation from Gαi. Our observations suggest that NPD9055 targets Gαi and thus regulates Gβγ-dependent cellular processes, most likely by causing the dissociation of Gβγ from Gαi.</jats:p>

収録刊行物

参考文献 (32)*注記

もっと見る

関連研究データ

もっと見る

関連プロジェクト

もっと見る

キーワード

詳細情報 詳細情報について

問題の指摘

ページトップへ