電子冷凍顕微鏡で解明されたグリシン受容体機構

Juan Du¹, Wei Lü¹, Shenping Wu²

¹Vollum Institute, Oregon Health &Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA.

Nature

|September 8, 2015

まとめ

グライシン受容体 (GlyR) の高解像度構造は,ストリヒニンとグライシンが結合する方法を明らかにし,抑制神経伝達と神経学的障害のメカニズムを明らかにします.

科学分野:

神経科学
構造生物学
分子薬理学

背景:

ストリヒニンに敏感なグリシン受容体 (GlyR) は,中枢神経系における阻害性シナプス伝達に不可欠である.
GlyRの機能不全は,自閉症や超複合症などの神経疾患に関わっている.
GlyRの分子機構と薬理学の理解を妨げていた.

研究の目的:

ゼブラフィッシュα1 GlyRの高解像度構造を異なるリガンドとの複合体で決定する.
GlyRの活性化,対抗性,および潜在的無敏感化の構造的基礎を解明する.
関連するCysループ受容体の構造を解釈するための枠組みを提供する.

主な方法:

電子冷凍顕微鏡 (cryo-EM) を使って構造を解析した.
ストリヒニン (対抗剤),グリシン (抗剤),およびグリシン/イヴァルメクチンの組み合わせに結合するGlyRの構造を決定した.

主要な成果:

ストリヒニンの結合は,結合ポケットを広げ,イオンチャネルを遮断することによって,GlyRを閉じた状態に閉じます.
グリシン結合は,GlyRをオープンチャネル形状で安定させる.
グリシン/イヴァルメクチンの複合体は,無感化または部分的に開かれた状態を示唆します.

結論:

決定された構造は,リガンド結合時にGlyRの異なる構成状態を明らかにする.
これらの発見は,GlyR機能と薬によるその調節の基礎となる分子メカニズムを明らかにします.
この研究は,Cysループ受容体の構成動態を理解するための構造的ルールを提供している.

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