RRC ID 48802
著者 Kawashima SA, Chen Z, Aoi Y, Patgiri A, Kobayashi Y, Nurse P, Kapoor TM.
タイトル Potent, Reversible, and Specific Chemical Inhibitors of Eukaryotic Ribosome Biogenesis.
ジャーナル Cell
Abstract All cellular proteins are synthesized by ribosomes, whose biogenesis in eukaryotes is a complex multi-step process completed within minutes. Several chemical inhibitors of ribosome function are available and used as tools or drugs. By contrast, we lack potent validated chemical probes to analyze the dynamics of eukaryotic ribosome assembly. Here, we combine chemical and genetic approaches to discover ribozinoindoles (or Rbins), potent and reversible triazinoindole-based inhibitors of eukaryotic ribosome biogenesis. Analyses of Rbin sensitivity and resistance conferring mutations in fission yeast, along with biochemical assays with recombinant proteins, provide evidence that Rbins' physiological target is Midasin, an essential ∼540-kDa AAA+ (ATPases associated with diverse cellular activities) protein. Using Rbins to acutely inhibit or activate Midasin function, in parallel experiments with inhibitor-sensitive or inhibitor-resistant cells, we uncover Midasin's role in assembling Nsa1 particles, nucleolar precursors of the 60S subunit. Together, our findings demonstrate that Rbins are powerful probes for eukaryotic ribosome assembly.
巻・号 167(2)
ページ 512-524.e14
公開日 2016-10-6
DOI 10.1016/j.cell.2016.08.070
PII S0092-8674(16)31168-0
PMID 27667686
PMC PMC5116814
MeSH Adenosine Triphosphatases / antagonists & inhibitors* Enzyme Inhibitors / chemistry Enzyme Inhibitors / isolation & purification Enzyme Inhibitors / pharmacology* Indoles / chemistry Indoles / isolation & purification Indoles / pharmacology* Ribosome Subunits, Large, Eukaryotic / drug effects* Ribosome Subunits, Large, Eukaryotic / metabolism* Schizosaccharomyces / drug effects Schizosaccharomyces / metabolism Schizosaccharomyces pombe Proteins / antagonists & inhibitors* Structure-Activity Relationship Triazines / chemistry Triazines / isolation & purification Triazines / pharmacology*
IF 38.637
引用数 19
WOS 分野 BIOCHEMISTRY & MOLECULAR BIOLOGY CELL BIOLOGY
リソース情報
遺伝子材料 S. pombe ORFeome clone SpYFH50A03 (SPW100003)