脂質Gタンパク質結合受容体の結晶構造
Michael A Hanson1, Christopher B Roth, Euijung Jo
1Receptos, 10835 Road to the Cure, San Diego, CA 92121, USA. mhanson@receptos.com
まとめ
スフィンゴシン1-リン酸受容体1 (S1P(1) の結晶構造は,抗生物質が結合する方法を示しています. リガンドは受容体にアクセスする.
科学分野:
- バイオケミストリー バイオケミストリー
- 構造生物学 構造生物学とは
- 薬理学 薬理学とは
背景:
- スフィンゴシン1-リン酸 (S1P) は,生物活性な脂質媒介体である.
- S1P受容体は,免疫細胞の密輸と血管の発達を含む重要な生理学的プロセスを調節する.
- S1P受容体の活性化を理解することは,治療の開発の鍵です.
研究 の 目的:
- アンタゴニストと結合したスフィンゴシン1-リン酸受容体1 (S1P(1) の結晶構造を決定する.
- S1P(1) 結合ポケットへのリガンドアクセスメカニズムを解明する.
- S1Pの分子認識と活性化に関する洞察を提供するために.
主な方法:
- S1P(1) がT4-リゾ酵素 (S1P(1) -T4Lと融合したX線結晶は,スフィンゴリピド模倣抗体との複合体である.
- サイト・ディレクテッド・ミュータジェネシス.
- アゴニストによる構造活動関係 (SAR) 研究.
- 分子モデリング.
主要な成果:
- 結晶構造は,閉ざされた細胞外結合ポケット入り口を明らかにします.
- 結合部位へのリガンドのアクセスは,トランスメブランヘリックスIとVIIの間の横方向に発生します.
- この構造は,S1Pの分子認識とS1Pの活性化における水性体積の必要性を明らかにしています.
結論:
- 決定された構造は,S1P ((1) 抗体結合の詳細な分子視点を提供します.
- これは,リガンドがS1Pにどのようにアクセスし,S1Pを活性化させるかについてのメカニズム的理解を提供します.
- この発見は,S1P受容体調節器の合理的な設計を促し,免疫細胞とストロマ細胞の反応を促進します.
関連する概念動画
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...
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...
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...


