異なる受容体構成を安定させる

Laura M Wingler¹, Matthias Elgeti², Daniel Hilger³

¹Department of Medicine and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.

Cell

|January 15, 2019

まとめ

バイアスGタンパク質結合受容体 (GPCR) アゴニストは,明確な構造変化を示す. この研究では,異なるリガンドが特定の受容体構造を安定させ,標的型GPCR薬の設計を支援することを明らかにした.

科学分野:

薬理学について
生物化学
構造生物学

背景:

Gタンパク質結合受容体 (GPCR) は重要な薬物標的である.
バイアスアゴニストは特定のシグナル伝達経路 (Gタンパク質またはβ-アレスティン) を活性化します.
リンガント誘発の形状の変化を理解することは,薬剤設計の鍵です.

研究の目的:

バイアスされたリガンドがアンジオテンシンII型I受容体 (AT1R) の構造変化をどのように変化させるかを調査する.
特定の受容体の形状をバイアス信号結果と相関させる.
GPCRを標的とした合理的な薬剤設計のための構造的基盤を提供すること.

主な方法:

二重電子共振 (DEER) スペクトロスコーピーを利用した.
AT1Rの窒素酸化物探査機で現場に指向されたスピンラベルを使用した.
細胞内領域のインタースピン距離をモニターし,コンフォメーション状態をマップします.

主要な成果:

AT1Rの4つの異なる形状を特定した.
リガンドの異なる機能クラスがユニークな形状分布を安定させることを示した.
Gqバイアスのアゴニストは"開いた"形状を安定させ,βアレスティンのバイアスのアゴニストは"遮断された"形状を好む.

結論:

AT1Rのリガンドバイアスは,構造的に異なる受容体構成にコード化されています.
DEERのスペクトロスコピーは,GPCRの構成動態を効果的にマッピングします.
これらの発見は,GPCRを標的とする薬の合理的な設計を可能にします.

キーワード:

ARB について DEER (鹿) について Gタンパク質結合受容体 GPCR についてアンジオテンシンII型1受容体アンジオテンシン受容体阻害剤ベータアレスティン偏ったアゴニズム形状選択二重電子共振スペクトロスコーピー機能的選択性ヘテロトリメリックGタンパク質分子ダイナミクスシミュレーション

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