哺乳類のGIRK2-βγ Gタンパク質複合体のX線構造
Matthew R Whorton1, Roderick MacKinnon
1Laboratory of Molecular Neurobiology and Biophysics, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA.
Nature
|June 7, 2013
まとめ
細胞の電気的興奮性に不可欠なGタンパク質ゲート内向整流器K ((+) (GIRK) チャンネルを構造的に分析した. この研究では,Gタンパク質サブユニットがGIRK2チャネルに結合し,開かれた状態を安定させ,チャネル活性化メカニズムを解明する方法を明らかにしました.
科学分野:
- 分子および細胞生物学
- 神経科学は神経科学である.
- バイオフィジックス 生物物理学
背景:
- Gタンパク質ゲート内側整流器K ((+)) (GIRK) チャンネルは,心臓および神経細胞の細胞の電気刺激性を調節する.
- これらのチャネルは,Gタンパク質結合受容体 (GPCRs) を通して信号を送る神経伝達物質によって活性化されます.
- Gタンパク質サブユニットとGIRKチャネルの相互作用は,このシグナル伝達経路の中心にある.
研究 の 目的:
- 哺乳類のGIRK2チャネルの高解像度結晶構造を,Gタンパク質 βγサブユニットとの複合体として決定する.
- Gタンパク質によるGIRKチャネル活性化の基礎となる構造的メカニズムを解明する.
- GIRKチャネル機能におけるPIP2やNa(+) などの調節性分子の役割を理解する.
主な方法:
- 3.5 Åの解像度のX線結晶学.
- GIRK2-Gタンパク質複合体の構造分析.
- チャンネル状態の構成分析. チャンネル状態の構成分析.
主要な成果:
- 結晶構造は,4つのβγGタンパク質サブユニットが,テトラメリックGIRK2チャネルのインターフェイスに結合していることを示しています.
- 特定の原子と静電相互作用により,チャンネルが前開かれた状態で安定します.
- この事前開かれた形状は,構造的に,閉じた状態と構成的に活発な開かれた状態の間の中間である.
結論:
- この発見は,GIRKチャネルのGタンパク質活性化のための"膜限定"モデルを支持する.
- この構造は,GIRKチャネルゲーティングの特徴的な爆破動力学についての洞察を提供します.
- この研究は,PIP2とNa2+) イオンによるGIRKチャネルのマルチリガンド調節を理解するための構造的基礎を提供します.
さらに関連する動画
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.
Assembly of Signaling Complexes
Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
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...
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...


