タリドミドと複合したDDB1-CRBN E3ユビキチンリガゼの構造
Eric S Fischer1, Kerstin Böhm1, John R Lydeard2
11] Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland [2] University of Basel, Petersplatz 10, CH-4003 Basel, Switzerland.
Nature
|July 22, 2014
まとめ
免疫調節薬 (IMiDs) は,過去のテロゲン性にもかかわらず,現在,CRL4 (CRBN) E3ユビキチンリガゼを標的としてがんを治療しています. 新しい構造は,IMiDsがCRBNを結合し,いくつかの基板をブロックし,他の基板を標的タンパク質の分解を促進する方法を明らかにします.
科学分野:
- バイオケミストリー バイオケミストリー
- 分子生物学は分子生物学である.
- ドラッグ・ディスカバリー・ディスカバリー・ドラッグ・ディスカバリー・ドラッグ・ディスカバリー
背景:
- タリドマイドおよびその誘導体 (レナリドマイド,ポマリドマイド) は,免疫調節薬 (IMiDs) として知られており,多発性骨髄腫および5q消去に関連した発育不良の効果的な治療法です.
- IMiDはテラトゲン性にもかかわらず,E3ユビキチンリガゼCUL4-RBX1-DDB1-CRBN (CRL4 ((CRBN)) を標的とする.
- CRL4 (CRBN) は,IKAROSファミリーの転写因子IKZF1とIKZF3.3のユビキチン化と分解を媒介する.
研究 の 目的:
- DDB1-CRBN複合体へのIMiD結合の構造的基礎を明らかにする.
- CRL4 ((CRBN)) の内生基板を特定するために.
- IMiDがCRL4 (CRBN) 活動を調節するメカニズムを理解する.
主な方法:
- X線結晶学を用いて,タリドミド,レーナリドミド,ポマリドミドに結合するDDB1-CRBN複合体の構造を決定した.
- CRL4 ((CRBN)) の内生基板を特定するために,偏りのないスクリーンが使用されました.
主要な成果:
- 結晶構造は,CRL4 ((CRBN) 内の基板受容体としてCRBNを明らかにし,IMiDsをエナチオ選択的に結合する.
- ホメオボックスの転写因子MEIS2は,CRL4の内生基質として識別されました.
- IMiDは,IKZF1またはIKZF3が分解のために採用される過程で,MEIS2のような内生基質がCRL4 (CRBN) に結合するのを阻害することが示されました.
結論:
- CRBNはCRL4の基板受容体として作用し,IMID結合と基板ユビキチネーションを媒介する.
- IMiDは, IKZF1/IKZF3の分解を促進し,MEIS2.2のような他の基板の分解を抑制する二重の活性を示しています.
- この二重メカニズムは,E3ユビキチンリガース活性を精密に調節する小分子の可能性を強調し,新しい治療戦略を提供します.
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