+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-29944 | |||||||||
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タイトル | Cryo-EM Structure of the Prostaglandin E2 Receptor 4 Coupled to G Protein | |||||||||
マップデータ | ||||||||||
試料 |
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キーワード | GPCR complex / SIGNALING PROTEIN | |||||||||
機能・相同性 | 機能・相同性情報 negative regulation of eosinophil extravasation / prostaglandin E receptor activity / Prostanoid ligand receptors / negative regulation of integrin activation / response to nematode / T-helper cell differentiation / regulation of stress fiber assembly / negative regulation of cytokine production / PKA activation in glucagon signalling / hair follicle placode formation ...negative regulation of eosinophil extravasation / prostaglandin E receptor activity / Prostanoid ligand receptors / negative regulation of integrin activation / response to nematode / T-helper cell differentiation / regulation of stress fiber assembly / negative regulation of cytokine production / PKA activation in glucagon signalling / hair follicle placode formation / developmental growth / regulation of ossification / D1 dopamine receptor binding / intracellular transport / renal water homeostasis / Hedgehog 'off' state / response to mechanical stimulus / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / JNK cascade / cellular response to glucagon stimulus / adenylate cyclase activator activity / ERK1 and ERK2 cascade / regulation of insulin secretion / trans-Golgi network membrane / positive regulation of cytokine production / negative regulation of inflammatory response to antigenic stimulus / bone development / G-protein beta/gamma-subunit complex binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / G protein activity / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / platelet aggregation / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / negative regulation of inflammatory response / cognition / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / cellular response to mechanical stimulus / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / positive regulation of inflammatory response / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / 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 / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / sensory perception of smell / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / positive regulation of cold-induced thermogenesis / retina development in camera-type eye / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / G alpha (i) signalling events / G alpha (s) 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 / G alpha (q) signalling events / Ras protein signal transduction / response to lipopolysaccharide / cell population proliferation / Extra-nuclear estrogen signaling / inflammatory response / immune response / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / protein-containing complex binding / GTP binding / signal transduction / extracellular exosome 類似検索 - 分子機能 | |||||||||
生物種 | Homo sapiens (ヒト) / Lama glama (ラマ) | |||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.3 Å | |||||||||
データ登録者 | Shenming H / Mengyao X / Lei L / Jiangqian M / Sheng C / Jinpeng S | |||||||||
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: 2023 タイトル: Single hormone or synthetic agonist induces G/G coupling selectivity of EP receptors via distinct binding modes and propagating paths. 著者: Shen-Ming Huang / Meng-Yao Xiong / Lei Liu / Jianqiang Mu / Ming-Wei Wang / Ying-Li Jia / Kui Cai / Lu Tie / Chao Zhang / Sheng Cao / Xin Wen / Jia-Le Wang / Sheng-Chao Guo / Yu Li / Chang- ...著者: Shen-Ming Huang / Meng-Yao Xiong / Lei Liu / Jianqiang Mu / Ming-Wei Wang / Ying-Li Jia / Kui Cai / Lu Tie / Chao Zhang / Sheng Cao / Xin Wen / Jia-Le Wang / Sheng-Chao Guo / Yu Li / Chang-Xiu Qu / Qing-Tao He / Bo-Yang Cai / Chenyang Xue / Shiyi Gan / Yihe Xie / Xin Cong / Zhao Yang / Wei Kong / Shuo Li / Zijian Li / Peng Xiao / Fan Yang / Xiao Yu / You-Fei Guan / Xiaoyan Zhang / Zhongmin Liu / Bao-Xue Yang / Yang Du / Jin-Peng Sun / 要旨: To accomplish concerted physiological reactions, nature has diversified functions of a single hormone at at least two primary levels: 1) Different receptors recognize the same hormone, and 2) ...To accomplish concerted physiological reactions, nature has diversified functions of a single hormone at at least two primary levels: 1) Different receptors recognize the same hormone, and 2) different cellular effectors couple to the same hormone-receptor pair [R.P. Xiao, , re15 (2001); L. Hein, J. D. Altman, B.K. Kobilka, , 181-184 (1999); Y. Daaka, L. M. Luttrell, R. J. Lefkowitz, , 88-91 (1997)]. Not only these questions lie in the heart of hormone actions and receptor signaling but also dissecting mechanisms underlying these questions could offer therapeutic routes for refractory diseases, such as kidney injury (KI) or X-linked nephrogenic diabetes insipidus (NDI). Here, we identified that G-biased signaling, but not G activation downstream of EP4, showed beneficial effects for both KI and NDI treatments. Notably, by solving Cryo-electron microscope (cryo-EM) structures of EP3-G, EP4-G, and EP4-G in complex with endogenous prostaglandin E (PGE)or two synthetic agonists and comparing with PGE-EP2-G structures, we found that unique primary sequences of prostaglandin E2 receptor (EP) receptors and distinct conformational states of the EP4 ligand pocket govern the G/G transducer coupling selectivity through different structural propagation paths, especially via TM6 and TM7, to generate selective cytoplasmic structural features. In particular, the orientation of the PGE ω-chain and two distinct pockets encompassing agonist L902688 of EP4 were differentiated by their G/G coupling ability. Further, we identified common and distinct features of cytoplasmic side of EP receptors for G/G coupling and provide a structural basis for selective and biased agonist design of EP4 with therapeutic potential. | |||||||||
履歴 |
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-構造の表示
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_29944.map.gz | 24.8 MB | EMDBマップデータ形式 | |
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ヘッダ (付随情報) | emd-29944-v30.xml emd-29944.xml | 21.8 KB 21.8 KB | 表示 表示 | EMDBヘッダ |
画像 | emd_29944.png | 84.5 KB | ||
Filedesc metadata | emd-29944.cif.gz | 7 KB | ||
その他 | emd_29944_half_map_1.map.gz emd_29944_half_map_2.map.gz | 7.3 MB 7.3 MB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-29944 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-29944 | HTTPS FTP |
-検証レポート
文書・要旨 | emd_29944_validation.pdf.gz | 535 KB | 表示 | EMDB検証レポート |
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文書・詳細版 | emd_29944_full_validation.pdf.gz | 534.6 KB | 表示 | |
XML形式データ | emd_29944_validation.xml.gz | 10.2 KB | 表示 | |
CIF形式データ | emd_29944_validation.cif.gz | 11.7 KB | 表示 | |
アーカイブディレクトリ | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-29944 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-29944 | HTTPS FTP |
-関連構造データ
-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 |
-マップ
ファイル | ダウンロード / ファイル: emd_29944.map.gz / 形式: CCP4 / 大きさ: 28.7 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: 1.7 Å | ||||||||||||||||||||||||||||||||||||
密度 |
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対称性 | 空間群: 1 | ||||||||||||||||||||||||||||||||||||
詳細 | EMDB XML:
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-添付データ
-ハーフマップ: #2
ファイル | emd_29944_half_map_1.map | ||||||||||||
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投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: #1
ファイル | emd_29944_half_map_2.map | ||||||||||||
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投影像・断面図 |
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密度ヒストグラム |
-試料の構成要素
-全体 : Prostaglandin E Receptor EP4 Coupled to G Protein
全体 | 名称: Prostaglandin E Receptor EP4 Coupled to G Protein |
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要素 |
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-超分子 #1: Prostaglandin E Receptor EP4 Coupled to G Protein
超分子 | 名称: Prostaglandin E Receptor EP4 Coupled to G Protein / 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: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
分子 | 名称: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short 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: 45.727441 KDa |
組換発現 | 生物種: Baculovirus expression vector pFastBac1-HM (ウイルス) |
配列 | 文字列: MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKNTIVKQM RILHVNGFNG EGGEEDPQAA RSNSDGEKA TKVQDIKNNL KEAIETIVAA MSNLVPPVEL ANPENQFRVD YILSVMNVPD FDFPPEFYEH AKALWEDEGV R ACYERSNE ...文字列: MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKNTIVKQM RILHVNGFNG EGGEEDPQAA RSNSDGEKA TKVQDIKNNL KEAIETIVAA MSNLVPPVEL ANPENQFRVD YILSVMNVPD FDFPPEFYEH AKALWEDEGV R ACYERSNE YQLIDCAQYF LDKIDVIKQD DYVPSDQDLL RCRVLTSGIF ETKFQVDKVN FHMFDVGAQR DERRKWIQCF ND VTAIIFV VASSSYNMVI REDNQTNRLQ AALKLFDSIW NNKWLRDTSV ILFLNKQDLL AEKVLAGKSK IEDYFPEFAR YTT PEDATP EPGEDPRVTR AKYFIRDEFL RISTASGDGR HYCYPHFTCA VDTENIRRVF NDCRDIIQRM HLRQYELL UniProtKB: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short |
-分子 #2: 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: 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: 38.458012 KDa |
組換発現 | 生物種: Baculovirus expression vector pFastBac1-HM (ウイルス) |
配列 | 文字列: LEVLFQGPGS SGSELDQLRQ EAEQLKNQIR DARKACADAT LSQITNNIDP VGRIQMRTRR TLRGHLAKIY AMHWGTDSRL LVSASQDGK LIIWDSYTTN KVHAIPLRSS WVMTCAYAPS GNYVACGGLD NICSIYNLKT REGNVRVSRE LAGHTGYLSC C RFLDDNQI ...文字列: LEVLFQGPGS SGSELDQLRQ EAEQLKNQIR DARKACADAT LSQITNNIDP VGRIQMRTRR TLRGHLAKIY AMHWGTDSRL LVSASQDGK LIIWDSYTTN KVHAIPLRSS WVMTCAYAPS GNYVACGGLD NICSIYNLKT REGNVRVSRE LAGHTGYLSC C RFLDDNQI VTSSGDTTCA LWDIETGQQT TTFTGHTGDV MSLSLAPDTR LFVSGACDAS AKLWDVREGM CRQTFTGHES DI NAICFFP NGNAFATGSD DATCRLFDLR ADQELMTYSH DNIICGITSV SFSKSGRLLL AGYDDFNCNV WDALKADRAG VLA GHDNRV SCLGVTDDGM AVATGSWDSF LKIWN UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 |
-分子 #3: Guanine nucleotide-binding protein subunit gamma
分子 | 名称: Guanine nucleotide-binding protein subunit gamma / 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: 12.104898 KDa |
組換発現 | 生物種: Baculovirus expression vector pFastBac1-HM (ウイルス) |
配列 | 文字列: MWRELPLGLG ELHKDHQASR KLEPELWSVS ENPPSTSMAS NNTASIAQAR KLVEQLKMEA NIDRIKVSKA AADLMAYCEA HAKEDPLLT PVPASENPFR EKKFFCAIL UniProtKB: Guanine nucleotide-binding protein subunit gamma |
-分子 #4: NB35
分子 | 名称: NB35 / 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: Lama glama (ラマ) |
分子量 | 理論値: 13.885439 KDa |
組換発現 | 生物種: unidentified (未定義) |
配列 | 文字列: QVQLQESGGG LVQPGGSLRL SCAASGFTFS NYKMNWVRQA PGKGLEWVSD ISQSGASISY TGSVKGRFTI SRDNAKNTLY LQMNSLKPE DTAVYYCARC PAPFTRDCFD VTSTTYAYRG QGTQVTVSS |
-分子 #5: Prostaglandin E2 receptor EP4 subtype
分子 | 名称: Prostaglandin E2 receptor EP4 subtype / 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: 53.173336 KDa |
組換発現 | 生物種: Baculovirus expression vector pFastBac1-HM (ウイルス) |
配列 | 文字列: MSTPGVNSSA SLSPDRLNSP VTIPAVMFIF GVVGNLVAIV VLCKSRKEQK ETTFYTLVCG LAVTDLLGTL LVSPVTIATY MKGQWPGGQ PLCEYSTFIL LFFSLSGLSI ICAMSVERYL AINHAYFYSH YVDKRLAGLT LFAVYASNVL FCALPNMGLG S SRLQYPDT ...文字列: MSTPGVNSSA SLSPDRLNSP VTIPAVMFIF GVVGNLVAIV VLCKSRKEQK ETTFYTLVCG LAVTDLLGTL LVSPVTIATY MKGQWPGGQ PLCEYSTFIL LFFSLSGLSI ICAMSVERYL AINHAYFYSH YVDKRLAGLT LFAVYASNVL FCALPNMGLG S SRLQYPDT WCFIDWTTNV TAHAAYSYMY AGFSSFLILA TVLCNVLVCG ALLRMHRQFM RRTSLGTEQH HAAAAASVAS RG HPAASPA LPRLSDFRRR RSFRRIAGAE IQMVILLIAT SLVVLICSIP LVVRVFVNQL YQPSLEREVS KNPDLQAIRI ASV NPILDP WIYILLRKTV LSKAIEKIKC LFCRIGGSRR ERSGQHCSDS QRTSSAMSGH SRSFISRELK EISSTSQTLL PDLS LPDLS ENGLGGRNLL PGVPGMGLAQ EDTTSLRTLR ISETSDSSQG QDSESVLLVD EAGGSGRAGP APKGSSLQVT FPSET LNLS EKCI UniProtKB: Prostaglandin E2 receptor EP4 subtype |
-分子 #6: (2S,5R)-5-[(1E,3S)-4,4-difluoro-3-hydroxy-4-phenylbut-1-en-1-yl]-...
分子 | 名称: (2S,5R)-5-[(1E,3S)-4,4-difluoro-3-hydroxy-4-phenylbut-1-en-1-yl]-1-[6-(1H-tetrazol-5-yl)hexyl]pyrrolidin-2-ol タイプ: ligand / ID: 6 / コピー数: 1 / 式: YZV |
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分子量 | 理論値: 421.484 Da |
Chemical component information | ChemComp-YZV: |
-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 |
-試料調製
緩衝液 | pH: 7.4 |
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凍結 | 凍結剤: ETHANE |
-電子顕微鏡法
顕微鏡 | FEI TITAN KRIOS |
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撮影 | フィルム・検出器のモデル: GATAN K3 (6k x 4k) / 平均電子線量: 25.0 e/Å2 |
電子線 | 加速電圧: 300 kV / 電子線源: OTHER |
電子光学系 | 照射モード: OTHER / 撮影モード: OTHER / 最大 デフォーカス(公称値): 2.0 µm / 最小 デフォーカス(公称値): 0.8 µm |
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |
-画像解析
初期モデル | モデルのタイプ: PDB ENTRY PDBモデル - PDB ID: |
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最終 再構成 | 解像度のタイプ: BY AUTHOR / 解像度: 3.3 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 使用した粒子像数: 279955 |
初期 角度割当 | タイプ: ANGULAR RECONSTITUTION |
最終 角度割当 | タイプ: PROJECTION MATCHING |