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Automated Counterflow Centrifugal System for Small-Scale Cell Processing
Published on: December 12, 2019
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胆酸トランスポーターにおける交替アクセスメカニズムの構造的基礎
Xiaoming Zhou1, Elena J Levin2, Yaping Pan3
11] Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA [2] Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA [3].
Nature
|December 10, 2013
まとめ
ASBTのような胆酸トランスポーターは,コレステロール代謝に不可欠であり,潜在的な薬物標的である. 新しい構造は,これらのトランスポーターが胆酸とナトリウムを膜に移動させ,薬の開発を支援する方法を明らかにします.
科学分野:
- バイオケミストリー バイオケミストリー
- 構造生物学 構造生物学とは
- メンブレーン輸送 メンブレーン輸送
背景:
- コレステロールから合成される胆汁酸は,脂質吸収に不可欠であり,腸肝循環を繰り返します.
- Na(+) に依存する胆酸トランスポーターであるNTCPとASBTは,ヒトにおける胆酸の再吸収を促進する.
- ASBTは,胆酸再吸収における役割のため,高コレステロール血症の重要な薬剤標的である.
研究 の 目的:
- ASBTによる胆酸とナトリウム輸送の分子機構を解明する.
- サブストラット選択性と輸送ダイナミクスの構造的基礎を理解する.
- ASBTを標的とする薬物の合理的な設計のための洞察を提供すること.
主な方法:
- 脂質環境におけるYersinia frederiksenii ASBT同型 (ASBTYf) の2つの結晶構造を決定した.
- Na(+) と胆酸の結合輸送に関連する構造変化を分析した.
- 輸送メカニズムと経路を推論するための比較構造.
主要な成果:
- ASBTYf.における基板結合ドメインの大きな硬体体回転を明らかにした.
- 膜の両側から保存された"クロスオーバー"領域の交替的なアクセシビリティが実証されています.
- 胆酸とNa ((+) 転位が膜を横切るための構造的基礎を提供した.
結論:
- 観測されたドメイン回転メカニズムは,ASBTが結合輸送をどのように促進するかを説明します.
- 構造的な洞察は,胆酸とNa ((+)) 移動の理解を促します.
- これらの発見は,コレステロール関連の疾患に対するASBTベースの治療法の開発を進めています.
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