原生生物系におけるプロテオーム全体の共性リガンドの発見
Keriann M Backus1, Bruno E Correia1, Kenneth M Lum1
1Department of Chemical Physiology, The Scripps Research Institute. La Jolla, California 92307, USA.
Nature
|June 17, 2016
まとめ
フラグメントベースの共性リガンドの発見は,以前は薬効性のないタンパク質のための700以上の新しい小分子探査機を特定しました. これらの新しい共性断片は特定のシステイン残基を標的とし,細胞システム内のタンパク質機能を照らします.
科学分野:
- 化学生物学
- 薬物の発見
- プロテオミクス
背景:
- タンパク質の機能の研究や 治療薬の開発には 小分子が不可欠です
- 多くのヒトのタンパク質には既知の小分子リガンドが欠けていて,従来のスクリーニング方法では"薬効性がない"状態になっています.
- コバレンスの断片は,難しいタンパク質の標的のリガンドを識別するための代替戦略を提供します.
研究 の 目的:
- ヒトのプロテオームと細胞に対してシステイン反応性小分子断片を定量的に分析する.
- 以前は薬剤で治療できなかったタンパク質の新しい共性リンガンドを発見し,非典型のリンガンド-タンパク質の相互作用を探求する.
- アポトーシスなどの生物学的経路を調査するために,同定された共性結合体を利用する.
主な方法:
- システイン反応性小分子断片を,タンパク質と細胞の何千ものヒトタンパク質に対してスクリーニングする.
- 断片とタンパク質の相互作用の定量分析
- 細胞系とT細胞の外部アポトーシス経路を分化するために,同定された共性リガンドを適用する.
主要な成果:
- 転写因子および特徴づけられていないタンパク質を含む様々なタンパク質の700以上のシステイン残基の共性リンガンドの識別.
- プロカスペス (非活性カスペス) と好ましい反応をする化合物の発見.
- ヒトの様々な細胞型における異なるカスパスによって媒介される外部アポトーシス経路の区別における共性リガンドの有用性の実証.
結論:
- フラグメントベースの共性リガンドの発見は,薬効性タンパク質の範囲を大幅に拡大します.
- このアプローチにより 複雑なタンパク質を標的にし その機能を解明できる 新しい化学的探査機が生まれます
- 複合的な生物学的過程の解剖に役立つ
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