グルカゴン受容体とグルカゴンアナログの複合体の構造
Haonan Zhang1,2,3, Anna Qiao1,2,3, Linlin Yang4
1CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China.
Nature
|January 5, 2018
まとめ
ヒトのグルカゴン受容体 (GCGR) がグルカゴン類に結合する構造を決定した. これは,重要な分子相互作用とGCGR活性化のための新しいモデルを明らかにし,クラスBのGタンパク質結合受容体 (GPCRs) の理解を進めています.
科学分野:
- 構造生物学
- 分子薬理学
- 生物化学
背景:
- クラスBのGタンパク質結合受容体 (GPCRs) は,ホルモンの恒常状態に不可欠であり,治療標的である.
- 既存のモデルは,ペプチドリガンドがB級GPCRの細胞外ドメイン (ECD) と細胞外ドメイン (TMD) に結合することを示唆している.
- 以前の構造研究は解像度と構造の柔軟性において制限があり,分子相互作用は曖昧であった.
研究 の 目的:
- ヒトのグルカゴン受容体 (GCGR) とそのペプチドリガンドの間の分子相互作用を解明する.
- クラスBのGPCR活性化に関する高解像度構造の洞察を提供すること.
- GCGRの活性化のための最新のモデルを提案する.
主な方法:
- ヒト全長グルカゴン受容体 (GCGR) とグルカゴン類型 (NNC1702) を複合したX線結晶図
- 受容体の細胞外領域 (ECD),膜外領域 (TMD),茎領域,細胞外ループにおける構造変化の分析.
- 不活性なGCGR複合体の以前に決定された構造との比較.
主要な成果:
- グルカゴンアナログに結合した全長ヒトGCGRの3. 0 Å解像度の結晶構造を決定した.
- GCGRとペプチドリガンドの間の詳細な分子相互作用を明らかにした.
- 重要なペプチド結合相互作用を形成する,茎と最初の細胞外ループの重要な形状の変化を観察した.
- GCGR ECDとTMDは,不活性状態と比較して,はっきりとした相対的方向性を特定した.
結論:
- この構造は,前例のないGCGR-ペプチド相互作用の分子詳細を提供します.
- GCGRの活性化のための二重結合部位トリガーモデルを提案し,茎,細胞外ループ,およびTMDの構造変化を伴う.
- このモデルは,クラスBのGPCRに対する確立された2ドメイン結合モデルを拡張し,受容体の活性化メカニズムに関する洞察を提供します.
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