マルチドラッグエクスポーターであるACRBの構造は,近隣のマルチサイト薬物結合ポケットを明らかにしています
Ryosuke Nakashima1, Keisuke Sakurai, Seiji Yamasaki
1Department of Cell Membrane Biology, Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Osaka 567-0047, Japan.
Nature
|November 29, 2011
まとめ
マルチドラッグトランスポーターAcrBには,薬物用の2つの異なる結合ポケットがあります. 高分子量抗生物質は2つのポケットを順番に使用しますが,低分子量薬は最初のポケットをバイパスします.
科学分野:
- 微生物学 微生物学とは
- 構造生物学 構造生物学とは
- バイオケミストリー バイオケミストリー
背景:
- AcrBは,抗生物質耐性において極めて重要な,グラム陰性細菌における重要な多剤輸送体である.
- AcrBは,AcrAとTolCとの三重複合体の一部として機能します.
- 以前の研究では,フェニララニンクラスター領域のいくつかの薬剤の結合部位を特定しました.
研究 の 目的:
- 高分子量薬であるリファンピシンとエリトロマイシンに結合するAcrBの結晶構造を決定する.
- 薬剤結合メカニズムを解明し,AcrB.内の異なる結合ポケットを特定する.
主な方法:
- X線結晶学を用いて,リファンピシンとエリトロミシンと複合したAcrBの構造を得ました.
- 結晶構造の分析により,薬物結合部位と相互作用が明らかになった.
主要な成果:
- AcrBの分子内経路に沿って2つの離散的なマルチサイト結合ポケットが特定されました:近接ポケットと遠隔ポケット (フェニララニンクラスター領域).
- 高分子量薬は順番に結合する:まずは,アクセス状態の近辺ポケットに結合し,次に,周回性メカニズムを通じて遠端ポケットに結合する.
- 低分子量薬は近辺のポケットをバイパスし,遠端のポケットに直接結合します.
結論:
- AcrBには2つの異なる結合ポケットがあり,その広範な基板認識を説明します.
- サブドメインの動きを含む環静止機構は,高分子量薬の輸送を容易にする.
- AcrBの結合メカニズムを理解することで,抗生物質耐性や薬剤開発の洞察が得られます.
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