多剤耐性HIV-1プロテアゼのオープン構造は,結晶パッキングコンタクトによって安定させられる
Melinda Layten1, Viktor Hornak, Carlos Simmerling
1Program in Molecular and Cellular Biology, Department of Chemistry, and Center for Structural Biology, Stony Brook University, Stony Brook, NY 11794, USA.
Journal of the American Chemical Society
|October 13, 2006
まとめ
HIV-1プロテアゼ (HIV-PR) の新興薬剤耐性菌は,患者の生存を脅かしている. シミュレーションにより,最近報告された耐性HIV-PR変異体の開いた結晶構造は不安定で,おそらく人工物であり,耐性メカニズムを説明していないことが明らかになった.
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
- コンピュータ生物学 コンピュータ生物学
背景:
- HIV-1プロテアゼ (HIV-PR) 阻害剤は患者の生存率を向上させましたが,薬剤耐性菌株による課題に直面しています.
- HIV-PRのダイナミクスとレジスタンス変異の理解は,新しい阻害剤の設計に不可欠です.
研究 の 目的:
- 多剤耐性 (MDR) 769 HIV-PR変異体の構造的動態を調査する.
- 最近報告されたMDR 769 HIV-PRの開いた結晶構造 (PDB:1TW7) が薬剤耐性に対する関連性を評価する.
主な方法:
- HIV-PR変異体MDR 769の分子動態シミュレーション.
- 溶液中のプロテアゼの構成動態の分析.
主要な成果:
- 報告されているMDR 769 HIV-PRの開いた結晶構造は溶液では不安定で,野生型無結合プロテアゼに似た半開いた形状を急速に採用している.
- MDR 769の結晶構造における観測された開いた状態は,おそらく,結晶の詰め合わせの人工物であり,配列の変化ではない.
- この構造は,阻害剤の侵入またはHIV-PR薬剤耐性の原因を正確に表さない場合があります.
結論:
- MDR 769の結晶構造に観察された開いた結合ポケットは,溶液中のプロテアズの振る舞いを表すものではありません.
- MDR 769 単離物の耐薬性の原因は,この結晶構造が示唆しているように,フラップの閉塞を誘導する阻害剤の無能力と直接に関連していないかもしれません.
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