M3マスカリン酸アセチルコリン受容体の構造と動態
Andrew C Kruse1, Jianxin Hu, Albert C Pan
1Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, California 94305, USA.
Nature
|February 24, 2012
まとめ
研究者は,チオトロピウムに結合するM3マスカリン性アセチルコリン受容体 (mAChR) の構造を決定した. この発見は,M2受容体データとともに,ムスカリン酸アセチルコリン受容体のための選択リガンドの設計に役立ちます.
科学分野:
- 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
- 構造生物学 構造生物学とは
背景:
- ムスカリン性アセチルコリン受容体 (mAChRs) は,アセチルコリンの生理学的効果を媒介するGタンパク質結合受容体 (GPCRs) である.
- 5つのmAChRサブタイプ (M1-M5) が存在し,Gタンパク質の結合と機能によって異なっているが,選択的な薬は依然として難解である.
研究 の 目的:
- チオトロピウムに結合したM3 mAChRの構造を決定する.
- M2とM3のmAChRの構造を比較して,異なるGタンパク質結合を理解する.
- 薬剤設計のための潜在的なアロステリック結合モードを探求する.
主な方法:
- X線結晶学を用いて,M3 mAChR-チオトロピウム複合体の構造を決定した.
- リガンド結合運動と経路を分析するために,分子動力学シミュレーションを実施した.
- M2受容体とM3受容体の構造を比較した分析を行いました.
主要な成果:
- ブロンコディレーターチオトロピウムがM3 mAChRに結合する方法が明らかにされました.
- 構造的な比較により,M2受容体とM3受容体間のGタンパク質結合機構の違いが明らかになった.
- 分子動力学シミュレーションでは,ティオトロピウムがアロステリック部位に一時的に結合することが示されています.
結論:
- 決定されたM3 mAChR構造は,亜型選択性リガンドの設計のための基礎を提供します.
- アロステル結合モードの理解は,mAChRsを標的とした治療法の開発のための新しい戦略を提供します.
- これらの発見は,GPCRsの構造的な理解を進めて,重要な受容体のための薬剤発見の改善を促進します.
関連する概念動画
01:25Cholinergic Receptors: Muscarinic
The pharmacological actions of acetylcholine are elicited via its binding to two families of cholinergic receptors or cholinoceptors, namely, muscarinic and nicotinic receptors. Muscarinic receptors are G protein-coupled receptors and have five subtypes, M1–M5. All mAChR subtypes are activated by acetylcholine and blocked by the antagonist, atropine.
The subtypes M1, M3, and M5 couple with the Gq subunit and activate the phospholipase C (PLC) activity, mobilizing intracellular Ca2+. Activation...
The subtypes M1, M3, and M5 couple with the Gq subunit and activate the phospholipase C (PLC) activity, mobilizing intracellular Ca2+. Activation...
01:15Cholinergic Receptors: Nicotinic
Nicotinic receptors are ligand-gated ion channels that are activated by acetylcholine and nicotine. Upon activation, they cause a rapid increase in the permeability of cells to K+, Na+, and Ca2+, followed by depolarization and excitation. They are in the autonomic ganglia, skeletal neuromuscular junction, CNS, and adrenal medulla.
There are two types of nicotinic receptors: neuromuscular (NM/NM/N1) and neuronal (NN/NN/N2). The two families differ based on their location and selectivity to...
There are two types of nicotinic receptors: neuromuscular (NM/NM/N1) and neuronal (NN/NN/N2). The two families differ based on their location and selectivity to...
01:22Direct-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship
Cholinergic agonists or cholinomimetics mimic the action of acetylcholine to stimulate the parasympathetic nervous system. They are categorized into direct-acting and indirect-acting agents. The direct-acting cholinergic drugs induce the parasympathetic response by directly binding to the muscarinic or nicotine receptors. In comparison, the indirect-acting cholinergic drugs prevent acetylcholine hydrolysis, indirectly contributing to the extended parasympathetic response.
The direct-acting...
The direct-acting...
01:29Cholinergic Antagonists: Chemistry and Structure-Activity Relationship
Cholinergic antagonists bind to cholinergic receptors and limit the effects of acetylcholine and other cholinergic agonists. Based on the specific cholinergic receptor affinity, these antagonists are classified as muscarinic or nicotinic. Anticholinergics interrupt parasympathetic innervations while sympathetic innervations remain uninterrupted. Muscarinic antagonists are also called 'muscarinic antagonists', 'antimuscarinics', or 'parasympatholytics'. Nicotinic antagonists are called...
01:29Indirect-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship
Indirect-acting cholinergic agonists are agents that interact with the acetylcholinesterase enzyme in the synaptic cleft, preventing the breakdown of acetylcholine into choline and acetate. Consequently, the concentration of acetylcholine in the synaptic cleft increases. These agonists can be classified into reversible and irreversible inhibitors based on their duration of action.
Reversible inhibitors display short to medium durations of action. Short-acting agents include simple alcohols with...
Reversible inhibitors display short to medium durations of action. Short-acting agents include simple alcohols with...
01:30Parasympathetic Signaling
Parasympathetic signaling plays a crucial role in regulating various physiological processes. It involves the release of acetylcholine (ACh) by parasympathetic neurons, which can have localized and short-lived effects. The majority of ACh released is rapidly inactivated at the synapse by the enzyme acetylcholinesterase (AChE), which hydrolyzes Ach into choline and acetate. Additionally, the tissue cholinesterase deactivates any ACh diffusing into the surrounding tissues.
The effects of...
The effects of...