MATE マルチドラッグ トランスポーターによる薬物挤出機構の構造的基礎
Yoshiki Tanaka1, Christopher J Hipolito, Andrés D Maturana
1RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
Nature
|March 29, 2013
まとめ
研究者らは,重要な多剤および有毒化合物挤出 (MATE) トランスポーターの構造を解明し,薬物挤出のメカニズムを明らかにし,治療用途のための強力なペプチド阻害剤を特定しました.
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
- 分子生物学は分子生物学である.
背景:
- マルチドラッグおよび有毒化合物挤出 (MATE) トランスポーターは,異種生物の流出に関与する重要な膜タンパク質です.
- これらのトランスポーターは,細菌の病原体と癌細胞の多剤耐性に貢献し,薬剤の有効性を制限します.
- MATEトランスポーター阻害剤の開発は,治療結果を改善するために不可欠です.
研究 の 目的:
- Pyrococcus furiosus.の H ((+)) 駆動の MATE トランスポーターの高解像度結晶構造を決定するために.
- 基板挤出および小分子およびペプチドによる抑制の基礎となる構造的メカニズムを解明する.
- 新種のMATE阻害剤の開発のための潜在的な鉛化合物を特定する.
主な方法:
- X線結晶学を用いて,MATEトランスポーターの構造をアポ形と複合状態で得られた.
- 構造的な特徴が輸送業者の活動に与える影響を評価するために,機能的分析が行われました.
- 抑制的可能性のあるチオエテル-マクロサイクリックペプチドを特定するために,インビトロ選択が使用されました.
主要な成果:
- P. furiosus MATEトランスポーターの2つの異なるアポ形構造が解明されました.
- 構造は,Asp 41のプロトネーションが,基板挤出につながる構造変化をどのように引き起こすかを明らかにしました.
- マクロサイクリックペプチドは中央裂け目に結合し,抑制効能と相関する明確な結合モードを示した.
結論:
- この研究は,MATE輸送媒介による薬物流出のメカニズムに関する詳細な構造的洞察を提供します.
- N-ロブ腔を標的とした強力なチオエテル-マクロサイクリックペプチド阻害剤が特定されました.
- これらの発見は,臨床応用のためのMATEトランスポーターに対する効果的な阻害剤を設計するための基礎を築く.
関連する概念動画
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