論文 - 詳細
| 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 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 19 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 遺伝子材料 | S. pombe ORFeome clone SpYFH50A03 (SPW100003) |