膜結合O-アシルトランスフェラーゼの結晶構造
Dan Ma1, Zhizhi Wang1, Christopher N Merrikh2
1Department of Biological Structure, University of Washington, Seattle, WA, USA.
Nature
|October 5, 2018
まとめ
結晶構造は,細菌の細胞壁改変に関与する膜結合O-アシルトランスファーゼ (MBOAT) の分子構造を明らかにする. これらの発見は,MBOATメカニズムを明らかにし,新しい治療的阻害剤の開発の基盤を提供します.
科学分野:
- 生物化学
- 構造生物学
- 微生物学
背景:
- 膜結合O-アシルトランスフェラーゼ (MBOAT) は,すべての生命体において不可欠なトランスメブラン酵素である.
- MBOATは,脂質生物合成,フォスフォリピド再構成,および分泌されるタンパク質の脂質改変において重要な役割を果たします.
- 薬物標的としての重要性にもかかわらず,MBOATの分子構造とメカニズムはほとんど特徴づけられていない.
研究 の 目的:
- バクテリアのMBOATであるDltBの結晶構造を単独で,そのD-アラニルドナータンパク質であるDltCと複合する.
- DltBの分子構造と機能的メカニズムの解明,特に細胞壁のテイコ酸のD-アラニル化におけるその役割.
- 異なる有機体におけるMBOATの保存された構造的核と触媒メカニズムに関する洞察を提供すること.
主な方法:
- DltBとその複合体とDltCの高解像度構造を取得するために,X線結晶学を用いた.
- サイト指向型変異は,触媒ヒスティジンとDLTC結合部位を含む主要な残留物の機能を調査するために使用されました.
- バクテリアのDltBと脊椎動物のMBOATの構造による配列比較が行われました.
主要な成果:
- 結晶構造はDltBが 細胞外トンネルを遮断する 11つの膜ヘリクスのリングを持っていることを示しています
- 保存された触媒ヒスティジン残留物は,トンネルを通してDltCに接続されている.
- 触媒ヒスティジンまたはDltC結合部位の変異はD-アラニレーションを廃止し,細胞壁へのストレスにBacillus subtilisを敏感にし,クロス膜触媒を示した.
結論:
- 決定された構造は,MBOATの分子構造とメカニズムに関する前例のない洞察を提供します.
- この発見は,様々な生物のMBOATに保存された構造的核と類似した触媒メカニズムを示唆している.
- これらの構造は,MBOAT構造-機能関係を理解し,MBOAT阻害剤の合理的な設計のためのテンプレートとして機能します.
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