隠された高アフィニティRNAコンフォーメーション状態を暴露する
Nicole I Orlovsky1, Hashim M Al-Hashimi1,2, Terrence G Oas1,2
1Department of Biochemistry , Duke University Medical Center , Durham , North Carolina 27710 , United States.
Journal of the American Chemical Society
|December 10, 2019
まとめ
RNA結合親和性を理解するには,形状的罰則を考慮する必要があります. この研究は,RNA-リガンド結合が全体的に弱い場合でも,特定のプリフォールドされたRNA状態に強い結合が関与し,薬物発見に影響を及ぼすことを明らかにしています.
科学分野:
- 生物化学
- 構造生物学
- 分子生物物理学
背景:
- RNA結合親和性は,構成変化と関連するエネルギーコストによって影響を受け",構成ペナルティ"と呼ばれます.
- これらの罰則を測定することは,結合されたRNA構成はしばしば結合されていない状態で検知できない集団を持っているため,困難です.
研究 の 目的:
- 結合RNAの構成変化とリガンド結合の熱力学モデルを開発する.
- HIV-1 TAR RNA-アルギニナミド (ARG) 相互作用モデルシステムにおける構成上の罰則を定量化する.
主な方法:
- 核磁気共鳴 (NMR) 化学シフトの乱れとリラクゼーションの分散を利用した.
- 低人口状態のエネルギーを推定するために12状態モデルにベイジアン推論を適用した.
- HIV-1 TAR RNAとアルギニナミド (ARG) の相互作用を,タットタンパク質の模倣として調査した.
主要な成果:
- TAR構成とARG占有率に基づいて,少なくとも4つの異なるRNA中間物質を特定した.
- 2つのARGリガンドを持つ支配的な結合された TAR構成は,検出限界以下の均衡集団が結合されていないことが明らかになった.
- ARGは,弱い表面的な全体的な親和度 (0. 2mM) にかかわらず,ナノモラー親和度で,前折れた TAR形状に結合することを実証した.
結論:
- 適合性罰則は,RNA-リガンド結合親和性を著しく決定し,結合協力性を誘導することができる.
- RNA認識の正確な予測には,形状転換のエネルギーコストを考慮する必要があります.
- この発見は,RNA標的薬の発見とRNA-タンパク質の相互作用の理解に意味を持つ.
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