人間のβ2アドレネルジックGタンパク質結合受容体の結晶構造
Søren G F Rasmussen1, Hee-Jung Choi, Daniel M Rosenbaum
1Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, Palo Alto, California 94305, USA.
Nature
|October 24, 2007
まとめ
研究者は,ヒトのベータ2アドレノ受容体 (ベータ2AR),重要なGタンパク質結合受容体 (GPCR) の構造を決定し,その不安定性と基礎活性に関する洞察を明らかにしました. これは,GPCRの構造生物学を進歩させています.
科学分野:
- 構造生物学 構造生物学とは
- バイオケミストリー バイオケミストリー
- 薬理学 薬理学とは
背景:
- Gタンパク質結合受容体 (GPCRs) は細胞シグナル伝達に不可欠ですが,構造的に研究することは困難です.
- 低豊富性,柔軟性,不安定性は,GPCRの構造分析を妨げています.
研究 の 目的:
- 人間のβ2アドレノ受容体 (β2AR) の高解像度構造を決定する.
- ベータ2ARの不安定性と基礎活性に対する構造的基礎を理解する.
主な方法:
- 逆アゴニストとFab断片を伴う脂質環境におけるβ2ARの結晶化.
- データ収集のための高輝度マイクロクリスタログラフィー.
- 3.4 A/3.7 A 解像度での構造決定.
主要な成果:
- 超膜セグメントの溶解した細胞質末端とβ2ARの連結ループ.
- ロドプシンと比較してベータ2ARでTM3とTM6の相互作用が弱いことが観察され,E/DRY配列を含む.
- ベータ2ARの細胞外領域は視覚化されませんでした.
結論:
- 決定されたβ2AR構造は,その高い基礎活性と不安定性のための分子基盤を提供します.
- ロドプシンとの差異は,ロドプシン以外のGPCRの結晶化における課題を強調しています.
- この研究は,GPCRの構造的理解と薬物開発を進める.
関連する概念動画
G-protein Coupled Receptors
G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.
G-protein Coupled Receptors
G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.
G Protein-coupled Receptors
G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
Activation and Inactivation of G Proteins
Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high affinity and are together...
G Protein-coupled Receptors
G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
Transducer Mechanism: G Protein–Coupled Receptors
G Protein–Coupled Receptors (GPCRs) are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to various stimuli. GPCRs regulate critical physiological pathways and are excellent drug targets for treating diseases such as diabetes, cancer, obesity, depression, or Alzheimer's. Nearly 35% of approved drugs implement their therapeutic effects by selectively interacting with specific GPCRs.
GPCRs are also called heptahelical, 7TM, or...
GPCRs are also called heptahelical, 7TM, or...


