非活性状態のヒトGABAB受容体の構造
Jinseo Park1, Ziao Fu2, Aurel Frangaj1
1Department of Pharmacology, Columbia University, New York, NY, USA.
Nature
|June 26, 2020
まとめ
GABAB受容体について
科学分野:
- 神経科学
- 分子生物学
- 構造生物学
背景:
- クラスCのGタンパク質結合受容体 (GPCR) であるGABAB受容体は,抑制性神経伝達に不可欠であり,神経学的状態と関連しています.
- GABAB1とGABAB2のヘテロダイマーとして機能し,それぞれはリガンド認識とGタンパク質結合において異なる役割を持っています.
- この重要な受容体の全長構造とトランスメブラン信号伝達メカニズムは不明のままでした.
研究 の 目的:
- 人間のGABAB受容体のほぼ全長構造を決定する.
- 不活性な形状とトランスメブラン信号の構造的基礎を解明する.
- 新しい構造的特徴とその機能的意味を特定する.
主な方法:
- 凍結電子顕微鏡 (cryo-EM) を使用して,ほぼ全長GABAB受容体の構造を捕捉した.
- 構造分析は,リガンド,サブユニットインターフェース,および主要な構成状態を特定することに焦点を当てました.
- 特定された構造要素の役割を調査するために,機能的アッセイが使用されました.
主要な成果:
- 非活性状態のGABAB受容体のほぼ全長構造が解明されました.
- 2つの内生性フォスフォリピドがトランスメブラン領域に埋め込まれ,受容体を安定させることが発見されました.
- トランスメブランヘリックス3と5の間の新しいヘテロダイマーインターフェースは",インターサブユニットラッチ"を特徴として,不活性な形状にとって重要であることが確認された.
結論:
- 決定された構造は,GABAB受容体の不活性状態に関する前例のない洞察を提供します.
- トランスメブランインターフェースと"インターサブユニットラッチ"は,受容体の静止の重要な決定因子である.
- このインターフェースの破壊は,GABAergicシグナリングの調節におけるその重要性を強調する構成受容体の活動につながります.
さらに関連する動画
関連する概念動画
Activation and Inactivation of G Proteins
10.2K
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...
10.2K
Ligand-Gated Ion Channel Receptor: Gating Mechanism
3.5K
Ligand-gated ion channels are transmembrane proteins that play a vital role in intercellular communication and functions of the nervous system. They allow the influx of ions across the membrane once the neurotransmitter binds, allowing the subsequent transmission of electrical excitation across the neurons. Other ligand-gated ion channels, like the γ-aminobutyric acid (GABA) receptor, permit anions like chloride into the cells on the binding of the GABA molecule. Their entry into the cell...
3.5K
G-protein Coupled Receptors
130.9K
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.
130.9K
G Protein-coupled Receptors
15.9K
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...
15.9K
Transducer Mechanism: G Protein–Coupled Receptors
3.6K
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,...
GPCRs are also called heptahelical,...
3.6K
G-Protein Gated Ion Channels
5.4K
GPCRs are primarily responsible for our sense of smell, taste, and vision. The binding of a sensory stimulus activates GPCR to stimulate effector proteins, many of which are ion channels in the sensory organs. GPCRs modulate the opening and closing of the target ion channels either directly by binding them, or by releasing second messengers that activate these channels. As ions move across the membrane, the membrane potential is altered, which induces an appropriate response.
Sensory...
Sensory...
5.4K


