+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 7vie | ||||||
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タイトル | Cryo-EM structure of Gi coupled Sphingosine 1-phosphate receptor bound with S1P | ||||||
要素 |
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キーワード | SIGNALING PROTEIN / GPCR / S1PR1 | ||||||
機能・相同性 | 機能・相同性情報 cardiac muscle tissue growth involved in heart morphogenesis / sphingosine-1-phosphate receptor activity / sphingolipid binding / blood vessel maturation / Lysosphingolipid and LPA receptors / endothelial cell differentiation / heart trabecula morphogenesis / regulation of bone mineralization / regulation of metabolic process / sphingosine-1-phosphate receptor signaling pathway ...cardiac muscle tissue growth involved in heart morphogenesis / sphingosine-1-phosphate receptor activity / sphingolipid binding / blood vessel maturation / Lysosphingolipid and LPA receptors / endothelial cell differentiation / heart trabecula morphogenesis / regulation of bone mineralization / regulation of metabolic process / sphingosine-1-phosphate receptor signaling pathway / leukocyte chemotaxis / regulation of bone resorption / lamellipodium assembly / positive regulation of positive chemotaxis / negative regulation of stress fiber assembly / transmission of nerve impulse / T cell migration / D2 dopamine receptor binding / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / regulation of cell adhesion / regulation of cAMP-mediated signaling / G protein-coupled serotonin receptor binding / cellular response to forskolin / regulation of mitotic spindle organization / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / Regulation of insulin secretion / G protein-coupled receptor binding / G protein-coupled receptor activity / adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of smooth muscle cell proliferation / brain development / neuron differentiation / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Glucagon signaling in metabolic regulation / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G beta:gamma signalling through CDC42 / response to peptide hormone / Vasopressin regulates renal water homeostasis via Aquaporins / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / G alpha (z) signalling events / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / GPER1 signaling / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / chemotaxis / GDP binding / cellular response to prostaglandin E stimulus / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / cell migration / signaling receptor complex adaptor activity / 加水分解酵素; 酸無水物に作用; GTPに作用・細胞または細胞小器官の運動に関与 / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / Ca2+ pathway / cell cortex / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / midbody / actin cytoskeleton organization / fibroblast proliferation / G alpha (s) signalling events / angiogenesis / Interleukin-4 and Interleukin-13 signaling / G alpha (q) signalling events / Ras protein signal transduction / Potential therapeutics for SARS / cell population proliferation / Extra-nuclear estrogen signaling / cell adhesion / endosome / positive regulation of cell migration / G protein-coupled receptor signaling pathway / membrane raft 類似検索 - 分子機能 | ||||||
生物種 | Homo sapiens (ヒト) Mus musculus (ハツカネズミ) | ||||||
手法 | 電子顕微鏡法 / 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 2.86 Å | ||||||
データ登録者 | Yu, L.Y. / Gan, B. / Xiao, Q.J. / Ren, R.B. | ||||||
資金援助 | 中国, 1件
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引用 | ジャーナル: Proc Natl Acad Sci U S A / 年: 2022 タイトル: Structural insights into sphingosine-1-phosphate receptor activation. 著者: Leiye Yu / Licong He / Bing Gan / Rujuan Ti / Qingjie Xiao / Hongli Hu / Lizhe Zhu / Sheng Wang / Ruobing Ren / 要旨: As a critical sphingolipid metabolite, sphingosine-1-phosphate (S1P) plays an essential role in immune and vascular systems. There are five S1P receptors, designated as S1PR1 to S1PR5, encoded in the ...As a critical sphingolipid metabolite, sphingosine-1-phosphate (S1P) plays an essential role in immune and vascular systems. There are five S1P receptors, designated as S1PR1 to S1PR5, encoded in the human genome, and their activities are governed by endogenous S1P, lipid-like S1P mimics, or nonlipid-like therapeutic molecules. Among S1PRs, S1PR1 stands out due to its nonredundant functions, such as the egress of T and B cells from the thymus and secondary lymphoid tissues, making it a potential therapeutic target. However, the structural basis of S1PR1 activation and regulation by various agonists remains unclear. Here, we report four atomic resolution cryo-electron microscopy (cryo-EM) structures of Gi-coupled human S1PR1 complexes: bound to endogenous agonist d18:1 S1P, benchmark lipid-like S1P mimic phosphorylated Fingolimod [(S)-FTY720-P], or nonlipid-like therapeutic molecule CBP-307 in two binding modes. Our results revealed the similarities and differences of activation of S1PR1 through distinct ligands binding to the amphiphilic orthosteric pocket. We also proposed a two-step “shallow to deep” transition process of CBP-307 for S1PR1 activation. Both binding modes of CBP-307 could activate S1PR1, but from shallow to deep transition may trigger the rotation of the N-terminal helix of Gαi and further stabilize the complex by increasing the Gαi interaction with the cell membrane. We combine with extensive biochemical analysis and molecular dynamic simulations to suggest key steps of S1P binding and receptor activation. The above results decipher the common feature of the S1PR1 agonist recognition and activation mechanism and will firmly promote the development of therapeutics targeting S1PRs. | ||||||
履歴 |
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-構造の表示
構造ビューア | 分子: MolmilJmol/JSmol |
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-ダウンロードとリンク
-ダウンロード
PDBx/mmCIF形式 | 7vie.cif.gz | 209 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb7vie.ent.gz | 165.1 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 7vie.json.gz | ツリー表示 | PDBx/mmJSON形式 | |
その他 | その他のダウンロード |
-検証レポート
文書・要旨 | 7vie_validation.pdf.gz | 853.4 KB | 表示 | wwPDB検証レポート |
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文書・詳細版 | 7vie_full_validation.pdf.gz | 866.7 KB | 表示 | |
XML形式データ | 7vie_validation.xml.gz | 36.3 KB | 表示 | |
CIF形式データ | 7vie_validation.cif.gz | 54.7 KB | 表示 | |
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/vi/7vie ftp://data.pdbj.org/pub/pdb/validation_reports/vi/7vie | HTTPS FTP |
-関連構造データ
-リンク
-集合体
登録構造単位 |
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1 |
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-要素
-Guanine nucleotide-binding protein ... , 3種, 3分子 ACD
#1: タンパク質 | 分子量: 39286.891 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: GNB1 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 参照: UniProt: P62873 |
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#2: タンパク質 | 分子量: 7861.143 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: GNG2 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 参照: UniProt: P59768 |
#5: タンパク質 | 分子量: 40415.031 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: GNAI1 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 参照: UniProt: P63096 |
-抗体 / タンパク質 / 非ポリマー , 3種, 3分子 EF
#3: 抗体 | 分子量: 26679.721 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Mus musculus (ハツカネズミ) / 発現宿主: Trichoplusia ni (イラクサキンウワバ) |
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#4: タンパク質 | 分子量: 44483.441 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: S1PR1, CHEDG1, EDG1 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 参照: UniProt: P21453 |
#6: 化合物 | ChemComp-S1P / ( |
-詳細
研究の焦点であるリガンドがあるか | Y |
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-実験情報
-実験
実験 | 手法: 電子顕微鏡法 |
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EM実験 | 試料の集合状態: PARTICLE / 3次元再構成法: 単粒子再構成法 |
-試料調製
構成要素 |
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由来(天然) |
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由来(組換発現) |
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緩衝液 | pH: 7.5 | ||||||||||||||||||||||||
試料 | 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES | ||||||||||||||||||||||||
急速凍結 | 凍結剤: ETHANE |
-電子顕微鏡撮影
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |
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顕微鏡 | モデル: FEI TITAN KRIOS |
電子銃 | 電子線源: FIELD EMISSION GUN / 加速電圧: 300 kV / 照射モード: FLOOD BEAM |
電子レンズ | モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 1900 nm / 最小 デフォーカス(公称値): 1100 nm |
撮影 | 電子線照射量: 56.14 e/Å2 / フィルム・検出器のモデル: GATAN K3 (6k x 4k) |
-解析
CTF補正 | タイプ: NONE |
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対称性 | 点対称性: C1 (非対称) |
3次元再構成 | 解像度: 2.86 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 922712 詳細: EVEN/ODD MAPS REFINED TOTALLY INDIPENDENT (GOLD STANDARD) for half map 対称性のタイプ: POINT |