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データを開く
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基本情報
| 登録情報 | データベース: EMDB / ID: EMD-32461 | |||||||||
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| タイトル | Cryo-EM of Sphingosine 1-phosphate receptor 1 / Gi complex bound to S1P | |||||||||
マップデータ | ||||||||||
試料 |
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キーワード | GPCR / MEMBRANE PROTEIN | |||||||||
| 機能・相同性 | 機能・相同性情報cardiac muscle tissue growth involved in heart morphogenesis / blood vessel maturation / sphingolipid binding / sphingosine-1-phosphate receptor activity / Lysosphingolipid and LPA receptors / endothelial cell differentiation / heart trabecula morphogenesis / regulation of bone mineralization / sphingosine-1-phosphate receptor signaling pathway / leukocyte chemotaxis ...cardiac muscle tissue growth involved in heart morphogenesis / blood vessel maturation / sphingolipid binding / sphingosine-1-phosphate receptor activity / Lysosphingolipid and LPA receptors / endothelial cell differentiation / heart trabecula morphogenesis / regulation of bone mineralization / sphingosine-1-phosphate receptor signaling pathway / leukocyte chemotaxis / positive regulation of positive chemotaxis / regulation of bone resorption / negative regulation of stress fiber assembly / regulation of metabolic process / lamellipodium assembly / transmission of nerve impulse / regulation of cell adhesion / adenylate cyclase inhibitor activity / positive regulation of protein localization to cell cortex / T cell migration / Adenylate cyclase inhibitory pathway / D2 dopamine receptor binding / response to prostaglandin E / G protein-coupled serotonin receptor binding / positive regulation of smooth muscle cell proliferation / adenylate cyclase regulator activity / adenylate cyclase-inhibiting serotonin receptor signaling pathway / cellular response to forskolin / regulation of mitotic spindle organization / Regulation of insulin secretion / positive regulation of cholesterol biosynthetic process / negative regulation of insulin secretion / G protein-coupled receptor binding / brain development / response to peptide hormone / G protein-coupled receptor activity / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / centriolar satellite / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / chemotaxis / neuron differentiation / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / G beta:gamma signalling through CDC42 / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / photoreceptor disc membrane / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / GDP binding / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / ADP signalling through P2Y purinoceptor 1 / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / G beta:gamma signalling through PI3Kgamma / cell migration / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / G-protein beta-subunit binding / cellular response to prostaglandin E stimulus / heterotrimeric G-protein complex / G alpha (12/13) signalling events / Inactivation, recovery and regulation of the phototransduction cascade / extracellular vesicle / sensory perception of taste / presynapse / Thrombin signalling through proteinase activated receptors (PARs) / signaling receptor complex adaptor activity / G protein activity / retina development in camera-type eye / actin cytoskeleton organization / GTPase binding / Ca2+ pathway / fibroblast proliferation / angiogenesis / Interleukin-4 and Interleukin-13 signaling / midbody / cell cortex / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / 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 類似検索 - 分子機能 | |||||||||
| 生物種 | Homo sapiens (ヒト) | |||||||||
| 手法 | 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 | EMマップ: SurfView Molmil Jmol/JSmol |
| 添付画像 |
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ダウンロードとリンク
-EMDBアーカイブ
| マップデータ | emd_32461.map.gz | 59.7 MB | EMDBマップデータ形式 | |
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| ヘッダ (付随情報) | emd-32461-v30.xml emd-32461.xml | 16.1 KB 16.1 KB | 表示 表示 | EMDBヘッダ |
| FSC (解像度算出) | emd_32461_fsc.xml | 9.1 KB | 表示 | FSCデータファイル |
| 画像 | emd_32461.png | 74.9 KB | ||
| Filedesc metadata | emd-32461.cif.gz | 6.7 KB | ||
| アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-32461 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-32461 | HTTPS FTP |
-関連構造データ
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リンク
| EMDBのページ | EMDB (EBI/PDBe) / EMDataResource |
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| 「今月の分子」の関連する項目 |
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マップ
| ファイル | ダウンロード / ファイル: emd_32461.map.gz / 形式: CCP4 / 大きさ: 64 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| 投影像・断面図 | 画像のコントロール
画像は Spider により作成 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ボクセルのサイズ | X=Y=Z: 1.1 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| 対称性 | 空間群: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 詳細 | EMDB XML:
CCP4マップ ヘッダ情報:
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-添付データ
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試料の構成要素
-全体 : S1PR1/Gi complex
| 全体 | 名称: S1PR1/Gi complex |
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| 要素 |
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-超分子 #1: S1PR1/Gi complex
| 超分子 | 名称: S1PR1/Gi complex / タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#5 |
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| 由来(天然) | 生物種: Homo sapiens (ヒト) |
-分子 #1: Sphingosine 1-phosphate receptor 1
| 分子 | 名称: Sphingosine 1-phosphate receptor 1 / タイプ: protein_or_peptide / ID: 1 / コピー数: 1 / 光学異性体: LEVO |
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| 由来(天然) | 生物種: Homo sapiens (ヒト) |
| 分子量 | 理論値: 42.898754 KDa |
| 組換発現 | 生物種: Insect BA phytoplasma (バクテリア) |
| 配列 | 文字列: MGPTSVPLVK AHRSSVSDYV NYDIIVRHYN YTGKLNISAD KENSIKLTSV VFILICCFII LENIFVLLTI WKTKKFHRPM YYFIGNLAL SDLLAGVAYT ANLLLSGATT YKLTPAQWFL REGSMFVALS ASVWSLLAIA IERYITMLKM KLHNGSNNFR L FLLISACW ...文字列: MGPTSVPLVK AHRSSVSDYV NYDIIVRHYN YTGKLNISAD KENSIKLTSV VFILICCFII LENIFVLLTI WKTKKFHRPM YYFIGNLAL SDLLAGVAYT ANLLLSGATT YKLTPAQWFL REGSMFVALS ASVWSLLAIA IERYITMLKM KLHNGSNNFR L FLLISACW VISLILGGLP IMGWNCISAL SSCSTVLPLY HKHYILFCTT VFTLLLLSIV ILYCRIYSLV RTRSRRLTFR KN ISKASRS SEKSLALLKT VIIVLSVFIA CWAPLFILLL LDVGCKVKTC DILFRAEYFL VLAVLNSGTN PIIYTLTNKE MRR AFIRIM SCCKCPSGDS AGKFKRPIIA GMEFSRSKSD NSSHPQKDEG DNPETIMSSG NVNSSS UniProtKB: Sphingosine 1-phosphate receptor 1 |
-分子 #2: Guanine nucleotide-binding protein G(i) subunit alpha-1
| 分子 | 名称: Guanine nucleotide-binding protein G(i) subunit alpha-1 タイプ: protein_or_peptide / ID: 2 / コピー数: 1 / 光学異性体: LEVO |
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| 由来(天然) | 生物種: Homo sapiens (ヒト) |
| 分子量 | 理論値: 40.445059 KDa |
| 組換発現 | 生物種: Insect BA phytoplasma (バクテリア) |
| 配列 | 文字列: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKSTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...文字列: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKSTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTTGIVETH FTFKDLHFKM FDVGAQRSER KKWIHCFEGV TAIIFCVALS DYDLVLAEDE EM NRMHESM KLFDSICNNK WFTDTSIILF LNKKDLFEEK IKKSPLTICY PEYAGSNTYE EAAAYIQCQF EDLNKRKDTK EIY THFTCS TDTKNVQFVF DAVTDVIIKN NLKDCGLF UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-1 |
-分子 #3: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
| 分子 | 名称: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 タイプ: protein_or_peptide / ID: 3 / コピー数: 1 / 光学異性体: LEVO |
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| 由来(天然) | 生物種: Homo sapiens (ヒト) |
| 分子量 | 理論値: 37.915496 KDa |
| 組換発現 | 生物種: Insect BA phytoplasma (バクテリア) |
| 配列 | 文字列: MGSLLQSELD QLRQEAEQLK NQIRDARKAC ADATLSQITN NIDPVGRIQM RTRRTLRGHL AKIYAMHWGT DSRLLVSASQ DGKLIIWDS YTTNKVHAIP LRSSWVMTCA YAPSGNYVAC GGLDNICSIY NLKTREGNVR VSRELAGHTG YLSCCRFLDD N QIVTSSGD ...文字列: MGSLLQSELD QLRQEAEQLK NQIRDARKAC ADATLSQITN NIDPVGRIQM RTRRTLRGHL AKIYAMHWGT DSRLLVSASQ DGKLIIWDS YTTNKVHAIP LRSSWVMTCA YAPSGNYVAC GGLDNICSIY NLKTREGNVR VSRELAGHTG YLSCCRFLDD N QIVTSSGD TTCALWDIET GQQTTTFTGH TGDVMSLSLA PDTRLFVSGA CDASAKLWDV REGMCRQTFT GHESDINAIC FF PNGNAFA TGSDDATCRL FDLRADQELM TYSHDNIICG ITSVSFSKSG RLLLAGYDDF NCNVWDALKA DRAGVLAGHD NRV SCLGVT DDGMAVATGS WDSFLKIWN UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 |
-分子 #4: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
| 分子 | 名称: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 タイプ: protein_or_peptide / ID: 4 / コピー数: 1 / 光学異性体: LEVO |
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| 由来(天然) | 生物種: Homo sapiens (ヒト) |
| 分子量 | 理論値: 7.861143 KDa |
| 組換発現 | 生物種: Insect BA phytoplasma (バクテリア) |
| 配列 | 文字列: MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 |
-分子 #5: scFv16
| 分子 | 名称: scFv16 / タイプ: protein_or_peptide / ID: 5 / コピー数: 1 / 光学異性体: LEVO |
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| 由来(天然) | 生物種: Homo sapiens (ヒト) |
| 分子量 | 理論値: 26.293299 KDa |
| 組換発現 | 生物種: Insect BA phytoplasma (バクテリア) |
| 配列 | 文字列: VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS AGGGGSGGGG SGGGGSSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS ...文字列: VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS AGGGGSGGGG SGGGGSSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS NGNTYLYWFL QRPGQSPQLL IYRMSNLASG VPDRFSGSGS GTAFTLTISR LEAEDVGVYY CMQHLEYPLT FG AGTKLEL |
-分子 #6: (2S,3R,4E)-2-amino-3-hydroxyoctadec-4-en-1-yl dihydrogen phosphate
| 分子 | 名称: (2S,3R,4E)-2-amino-3-hydroxyoctadec-4-en-1-yl dihydrogen phosphate タイプ: ligand / ID: 6 / コピー数: 1 / 式: S1P |
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| 分子量 | 理論値: 379.472 Da |
| Chemical component information | ![]() ChemComp-S1P: |
-実験情報
-構造解析
| 手法 | クライオ電子顕微鏡法 |
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解析 | 単粒子再構成法 |
| 試料の集合状態 | particle |
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試料調製
| 緩衝液 | pH: 7.5 |
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| 凍結 | 凍結剤: ETHANE / チャンバー内湿度: 98 % |
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電子顕微鏡法
| 顕微鏡 | FEI TITAN KRIOS |
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| 特殊光学系 | エネルギーフィルター - 名称: GIF Bioquantum |
| 撮影 | フィルム・検出器のモデル: GATAN K2 SUMMIT (4k x 4k) 検出モード: SUPER-RESOLUTION / 撮影したグリッド数: 1 / 平均電子線量: 60.0 e/Å2 |
| 電子線 | 加速電圧: 300 kV / 電子線源: FIELD EMISSION GUN |
| 電子光学系 | C2レンズ絞り径: 100.0 µm / 最小 デフォーカス(補正後): 1.2 µm / 照射モード: OTHER / 撮影モード: OTHER / Cs: 2.7 mm 最大 デフォーカス(公称値): 2.3000000000000003 µm 最小 デフォーカス(公称値): 1.2 µm |
| 実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |
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万見について



キーワード
Homo sapiens (ヒト)
データ登録者
中国, 1件
引用
UCSF Chimera









































Z (Sec.)
Y (Row.)
X (Col.)





















Insect BA phytoplasma (バクテリア)
解析


