多剤耐性タンパク質MRP1による基板認識の構造的基礎
Zachary Lee Johnson1, Jue Chen1
1Laboratory of Membrane Biology and Biophysics, The Rockefeller University and the Howard Hughes Medical Institute, 1230 York Avenue, New York, NY 10065, USA.
Cell
|February 28, 2017
まとめ
多剤耐性関連タンパク質1 (MRP1) トランスポーター
科学分野:
- 生物化学
- 分子生物学
- 構造生物学
背景:
- 多剤耐性タンパク質1 (MRP1) はATP結合カセット (ABC) トランスポーターである.
- MRP1は抗がん薬の耐性,薬の消化,炎症やホルモンの分泌などの生理学的プロセスに関与しています.
研究 の 目的:
- 牛のMRP1のアポ状態と基板結合状態の分子構造を決定する.
- MRP1における基質認識と形状の変化のメカニズムを解明する.
主な方法:
- 電子冷凍顕微鏡 (cryo-EM) を用いて,MRP1の構造を解析した.
- アポMRP1 (3. 5 Å) とルコトリエンC4 (3. 3 Å) と複合したMRP1の両方の高解像度構造が得られた.
主要な成果:
- 構造は,MRP1の単一の二重結合部位を明らかにし,様々な基板を収容することができます.
- レウコトリエンのC4結合は,ATPの水解のためにトランスポーターをプリミングして,重要な形状の変化を誘導する.
- P-グリコプロテインとの構造的比較は,多剤耐性に関連する保存され,独特な特徴を突出します.
結論:
- MRP1の二重結合部位は,その広範な基板特異性を説明する.
- MRP1の輸送メカニズムには,基板によって引き起こされる形状の変化が不可欠です.
- MRP1の構造-機能関係を理解することで,多剤耐性および化学療法有効性に関する洞察が進みます.
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