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リガンドフリー状態のFrizzled 4受容体の結晶構造

Shifan Yang¹, Yiran Wu¹, Ting-Hai Xu²

¹iHuman Institute, ShanghaiTech University, Shanghai, China.

|August 24, 2018

まとめ

Wntシグナル伝達に不可欠なFrizzled受容体 (FZD) は,従来のリガンド結合を阻害するユニークな構造を有する. この発見は,FZDを標的とする薬や探査機の開発における課題を説明するかもしれません.

科学分野:

構造生物学
生物化学
細胞シグナリング

背景:

フリズレド受容体 (Frizzled receptors,FZD) は,F級のGタンパク質結合受容体 (GPCRs) で,発達および成人生物におけるWnt信号伝達に不可欠である.
FZDはWntシグナル伝達における重要な媒介者として作用し,薬物開発と研究探査の重要なターゲットとなっています.

研究の目的:

人間Frizzled 4受容体 (FZD4) 経膜ドメインの結合リガンドなしの原子解像度構造を決定する.
FZDにおけるリガンド結合と活性化メカニズムの構造的基礎を調査する.

主な方法:

FZD4トランスメブラン領域の原子解像度構造を得るためのX線結晶学.
マイクロ秒のスケールで分子動力学シミュレーション
活性化に関与する主要な残留物と構造要素を特定するための変異分析

主要な成果:

FZD4の異常なトランスメブラン構造が明らかにされ,他のGPCRとは異なり,短く,密集したヘリックスVIがある.
伝統的なGPCRリガンドには適さない狭い水性結合ポケットが特定され,FZD全体に保存されていることが判明しました.
ヘリックスVIIの2つの動的歪みが発見され,FZD4の活性化に関わっている.

結論:

独特のFZD4構造とリガンド結合ポケットは,従来の薬の開発に課題をもたらします.
FZD間の保存された狭いポケットは,特定のリガンドの開発の困難を説明する可能性があります.
FZDは,ヘリックスVIIダイナミクスを含む他のGPCRとは異なる新しいリガンド認識およびアクティベーションメカニズムを使用する可能性があります.

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