+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 7wf7 | ||||||
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タイトル | Cryo-EM of Sphingosine 1-phosphate receptor 1 / Gi complex bound to S1P | ||||||
要素 |
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キーワード | MEMBRANE PROTEIN / GPCR | ||||||
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 / T cell migration / endothelial cell differentiation / heart trabecula morphogenesis / regulation of bone mineralization / regulation of metabolic process ...cardiac muscle tissue growth involved in heart morphogenesis / sphingosine-1-phosphate receptor activity / sphingolipid binding / blood vessel maturation / Lysosphingolipid and LPA receptors / T cell migration / 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 / positive regulation of positive chemotaxis / negative regulation of stress fiber assembly / lamellipodium assembly / transmission of nerve impulse / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / regulation of cell adhesion / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / regulation of mitotic spindle organization / cellular response to forskolin / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / positive regulation of smooth muscle cell proliferation / Regulation of insulin secretion / G protein-coupled receptor binding / G protein-coupled receptor activity / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / brain development / Activation of the phototransduction cascade / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / adenylate cyclase-activating G protein-coupled receptor signaling pathway / 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 / neuron differentiation / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / response to peptide hormone / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / GDP binding / chemotaxis / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / cell migration / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / cell cortex / midbody / G alpha (i) signalling events / fibroblast proliferation / actin cytoskeleton organization / G alpha (s) signalling events / Potential therapeutics for SARS / G alpha (q) signalling events / Ras protein signal transduction / Interleukin-4 and Interleukin-13 signaling / angiogenesis / Extra-nuclear estrogen signaling / cell population proliferation / endosome / cell adhesion / positive regulation of cell migration / membrane raft / G protein-coupled receptor signaling pathway / cell division 類似検索 - 分子機能 | ||||||
生物種 | Homo sapiens (ヒト) | ||||||
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: 3.4 Å | ||||||
データ登録者 | He, Y. / Xu, Z. | ||||||
資金援助 | 中国, 1件
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引用 | ジャーナル: Nat Chem Biol / 年: 2022 タイトル: Structural basis of sphingosine-1-phosphate receptor 1 activation and biased agonism. 著者: Zhenmei Xu / Tatsuya Ikuta / Kouki Kawakami / Ryoji Kise / Yu Qian / Ruixue Xia / Ming-Xia Sun / Anqi Zhang / Changyou Guo / Xue-Hui Cai / Zhiwei Huang / Asuka Inoue / Yuanzheng He / 要旨: Sphingosine-1-phosphate receptor 1 (S1PR1) is a master regulator of lymphocyte egress from the lymph node and an established drug target for multiple sclerosis (MS). Mechanistically, therapeutic ...Sphingosine-1-phosphate receptor 1 (S1PR1) is a master regulator of lymphocyte egress from the lymph node and an established drug target for multiple sclerosis (MS). Mechanistically, therapeutic S1PR1 modulators activate the receptor yet induce sustained internalization through a potent association with β-arrestin. However, a structural basis of biased agonism remains elusive. Here, we report the cryo-electron microscopy (cryo-EM) structures of G-bound S1PR1 in complex with S1P, fingolimod-phosphate (FTY720-P) and siponimod (BAF312). In combination with functional assays and molecular dynamics (MD) studies, we reveal that the β-arrestin-biased ligands direct a distinct activation path in S1PR1 through the extensive interplay between the PIF and the NPxxY motifs. Specifically, the intermediate flipping of W269 and the retained interaction between F265 and N307 are the key features of the β-arrestin bias. We further identify ligand-receptor interactions accounting for the S1PR subtype specificity of BAF312. These structural insights provide a rational basis for designing novel signaling-biased S1PR modulators. | ||||||
履歴 |
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-構造の表示
ムービー |
ムービービューア |
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構造ビューア | 分子: MolmilJmol/JSmol |
-ダウンロードとリンク
-ダウンロード
PDBx/mmCIF形式 | 7wf7.cif.gz | 194.3 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb7wf7.ent.gz | 155.4 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 7wf7.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
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/wf/7wf7 ftp://data.pdbj.org/pub/pdb/validation_reports/wf/7wf7 | HTTPS FTP |
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-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 BCD
#2: タンパク質 | 分子量: 40445.059 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: Insect BA phytoplasma (バクテリア) / 参照: UniProt: P63096 |
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#3: タンパク質 | 分子量: 37915.496 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: Insect BA phytoplasma (バクテリア) / 参照: UniProt: P62873 |
#4: 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: Insect BA phytoplasma (バクテリア) / 参照: UniProt: P59768 |
-タンパク質 / 抗体 / 非ポリマー , 3種, 3分子 AE
#1: タンパク質 | 分子量: 42898.754 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: Insect BA phytoplasma (バクテリア) / 参照: UniProt: P21453 |
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#5: 抗体 | 分子量: 26293.299 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 発現宿主: Insect BA phytoplasma (バクテリア) |
#6: 化合物 | ChemComp-S1P / ( |
-詳細
研究の焦点であるリガンドがあるか | N |
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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 | 名称: S1PR1/Gi complex / タイプ: COMPLEX / Entity ID: #1-#5 / 由来: RECOMBINANT |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
由来(組換発現) | 生物種: Insect BA phytoplasma (バクテリア) |
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 / 湿度: 98 % |
-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: OTHER |
電子レンズ | モード: OTHER / 最大 デフォーカス(公称値): 2300 nm / 最小 デフォーカス(公称値): 1200 nm / Calibrated defocus min: 1200 nm / Cs: 2.7 mm / C2レンズ絞り径: 100 µm |
撮影 | 電子線照射量: 60 e/Å2 / 検出モード: SUPER-RESOLUTION フィルム・検出器のモデル: GATAN K2 SUMMIT (4k x 4k) 撮影したグリッド数: 1 |
電子光学装置 | エネルギーフィルター名称: GIF Bioquantum |
EM回折 | カメラ長: 800 mm |
EM回折 シェル | 解像度: 3→5.5 Å / フーリエ空間範囲: 93.2 % / 多重度: 2.5 / 構造因子数: 244 / 位相残差: 13.5 ° |
EM回折 統計 | フーリエ空間範囲: 93 % / 再高解像度: 2.83 Å / 測定した強度の数: 1590 / 構造因子数: 325 / 位相誤差の除外基準: 20 / Rmerge: 0.198 |
-解析
EMソフトウェア |
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CTF補正 | タイプ: NONE | |||||||||
3次元再構成 | 解像度: 3.4 Å / 解像度の算出法: FSC 0.5 CUT-OFF / 粒子像の数: 500000 / 対称性のタイプ: POINT | |||||||||
原子モデル構築 | B value: 143 / プロトコル: AB INITIO MODEL / 空間: REAL | |||||||||
原子モデル構築 | PDB-ID: 6VMS PDB chain-ID: A |