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β(2) アドレノ受容体のナノボディ安定化活性状態の構造

Søren G F Rasmussen¹, Hee-Jung Choi, Juan Jose Fung

¹Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, California 94305, USA.

|January 14, 2011

まとめ

研究者は,ナノボディを使用して,活性Gタンパク質結合受容体 (GPCR) 状態を安定させました. これにより,アゴニストに結合した活性ベータ-2 アドレナリン受容体 (β(2) AR) の最初の結晶構造が得られ,重要な活性化メカニズムが明らかにされました.

科学分野:

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
薬理学薬理学とは

背景:

Gタンパク質結合受容体 (GPCR) は重要な薬物の標的ですが,その活性状態は不安定で,構造的に研究するのは困難です.
既存の結晶構造は,主に不活性なGPCR構成を表しています.
GPCRの活性化を理解することは,薬剤の発見と開発に不可欠です.

研究の目的:

アゴニスト結合活性状態のGPCRの高解像度結晶構造を取得する.
リンガンドによるGPCR活性化の基礎となる分子メカニズムを解明する.
GPCRシグナル伝達を理解するための構造的基礎を提供すること.

主な方法:

人間のβ-2アドレネルゲン受容体 (β(2) AR) を標的にするカメリド抗体断片 (ナノボディ) の生成.
アゴニストとの β(2) AR-ナノボディ複合体の共結晶化.
活性受容体ナノボディ複合体の構造を決定するX線結晶学.
活性構造と以前に決定された非活性β(2) AR構造の比較.

主要な成果:

ナノボディとの複合体におけるヒトβ(2) ARのアゴニストに結合した活性状態の結晶構造が得られました.
不活性状態との比較では,リガンド結合ポケット内の微妙だが重要な変化が明らかになった.
大規模な形状の変化は,トランスメブランセグメント6の細胞質末端の11 Åの外向きの動きを含んでいた.
トランスメブランセグメント5と7の再配置が観察され,アクティブオプシンにおける再配置を反映した.

結論:

ナノボディはβ(2) ARの活性構造を効果的に安定させ,構造的決定を可能にしました.
観察された構造の変化は,アゴニスト結合時のGPCR活性化の分子イベントに関する重要な洞察を提供します.
この研究は,GPCRスーパーファミリー全体のリガンド誘発活性化を理解するための構造的なテンプレートを提供します.

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