全長グリコタンパク質ホルモン受容体シグナル複合体の構造
Jia Duan1,2, Peiyu Xu1,2, Xi Cheng1
1The CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Nature
|September 23, 2021
まとめ
ルテイン化ホルモン・コリオゴナドトロピン受容体 (LHCGR) の活性化に関する構造的な洞察は,新しい
科学分野:
- 構造生物学
- 内分泌学
- 分子薬理学
背景:
- ルテイン化ホルモン (LH) と胆管性ホルモン (CG) は,生殖に不可欠なグリコタンパク質ホルモンです.
- これらのホルモンは,Gタンパク質結合受容体であるルテイン化ホルモン・コリオゴナドトロピン受容体 (LHCGR) を活性化させます.
- LHCGRは内分泌系疾患における治療介入の重要なターゲットです.
研究 の 目的:
- LHとCGによるLHCGR活性化の構造的メカニズムを解明する.
- 受容体のシグナル伝達における保存されたヒンジ領域の役割を理解する.
- LHCGRを標的とする新薬の開発のための構造的基盤を提供すること.
主な方法:
- LHCGRの4つの異なる構造を決定するために,冷凍電子顕微鏡 (cryo-EM) が使用されました.
- 構造は,非活性および活性状態の野生型LHCGRと,構成的に活発な変異体で捕獲されました.
- 複合的な構造には,結合したCG,Gsタンパク質,およびアロステリックアゴニスト (Org43553) が含まれていた.
主要な成果:
- ホルモン結合とヒンジループのダイナミクスを含む受容体活性化の"プッシュ・アンド・プル"メカニズムが特定されました.
- ハンドルループの保存された10残基断片 (P10) は,結合アゴニストとして作用し,トランスメブラン領域の構成変化を誘導する.
- アロステリックアゴニストであるOrg43553は,P10断片と相互作用することで,活性受容体構成を安定させる.
結論:
- これらの構造は,グリコプロテインホルモン受容体のシグナル伝達を理解するための統一モデルを提供します.
- この発見は,LHCGRの活性化とアロステル調節に関する重要な洞察を提供します.
- この研究は,内分泌障害を標的とした構造ベースの薬の発見の基礎をなしています.
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