ニューロテンシン受容体1型集合体に対するリガンドとトランスデューサの作用
Austin D Dixon1, Asuka Inoue2, Scott A Robson1
1Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, Indiana 47405, United States.
Journal of the American Chemical Society
|June 1, 2022
まとめ
ニューロテンシン受容体1 (NTS1) は複数の形状に存在する. ベータアレスティン-1 と Gαq のようなリガンドとトランスデューサは,これらの構造を動的に変化させ,受容体の活性化メカニズムに影響を与えます.
科学分野:
- 生物化学
- 構造生物学
- 薬理学について
背景:
- ニューロテンシン受容体1 (NTS1) のようなGタンパク質結合受容体 (GPCR) は,細胞信号伝達において重要な役割を果たします.
- NTS1の動的構成状態を理解することは,その活性化メカニズムの解明の鍵です.
研究 の 目的:
- リガンドとトランスデューサが溶液中のNTS1の構造アンサンブルをどのように調節するかを調査する.
- NTS1の構成部分と交換ダイナミクスを特徴づける.
主な方法:
- NTS1のトランスメブランヘリックス6でフッ素-19 (19F) 核磁気共鳴 (NMR) 探査機を使用した.
- 構成交換プロセスを分析するために動的NMR実験を行った.
主要な成果:
- Apo NTS1は,ミリ秒から秒間の時間スケール交換で,少なくとも3つのコンフォメーションサブステート (無活性および2つの活性型) の均衡状態に存在する.
- オーソステリックリガンドは,これらのサブステートの熱力学および運動的特性を再構築する.
- β-アレスティン-1またはGαqペプチドとの結合は,不活性な基質を廃止し,既存の活性状態を βArr1 で選択し,新しい状態を Gαq で誘導します.
結論:
- NTS1の活性化には,単一の静的な構造ではなく,ダイナミックな形状の集合が含まれています.
- アロステル活性化メカニズムは,結合されたトランスデューサに依存して,誘導された適合または構成選択によって影響を受けます.
- 静的な構造モデルは,受容体の溶液アンサンブルとダイナミクスを完全に表現しない場合があります.
関連する概念動画
The Two-State Receptor Model
2.5K
The two-state receptor model explains a drug's interaction with receptors, such as G protein-coupled receptors and ligand-gated ion channels, to induce or inhibit a biological response. When no natural ligands are present, a receptor exists in an equilibrium of inactive (Ri) and active (Ra) conformations. The inactive form does not produce a response, while the active form generates a basal effect known as constitutive activity.
The binding affinity of a drug determines its interaction with...
The binding affinity of a drug determines its interaction with...
2.5K
Ligand-Gated Ion Channel Receptor: Gating Mechanism
2.7K
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...
2.7K
Transducer Mechanism: G Protein–Coupled Receptors
2.6K
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,...
2.6K
Ligand-gated Ion Channels
12.8K
Ligand-gated ion channels are transmembrane proteins with a channel for ions to pass through and a binding site for a ligand. The channel opens only when a ligand attaches to the binding site.
Three Subfamilies of Ligand-gated Ion Channels
Ligand-gated ion channels fall into three subfamilies. The 'Cys-loop' includes the nicotinic acetylcholine receptors, γ-aminobutyric acid (GABA), glycine, and 5-hydroxytryptamine receptors. The second one is the 'Pore-loop' channels that...
Three Subfamilies of Ligand-gated Ion Channels
Ligand-gated ion channels fall into three subfamilies. The 'Cys-loop' includes the nicotinic acetylcholine receptors, γ-aminobutyric acid (GABA), glycine, and 5-hydroxytryptamine receptors. The second one is the 'Pore-loop' channels that...
12.8K
Ligand Binding Sites
13.6K
Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
13.6K
Ligand Binding and Linkage
5.0K
Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked. In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
5.0K


