+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-36175 | |||||||||
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タイトル | Cryo-EM structure of G protein-free mGlu2-mGlu4 heterodimer in Acc state | |||||||||
マップデータ | ||||||||||
試料 |
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キーワード | Complex structure / mGlu2-mGlu4 heterodimer / MEMBRANE PROTEIN | |||||||||
機能・相同性 | 機能・相同性情報 adenylate cyclase-inhibiting G protein-coupled glutamate receptor signaling pathway / cellular component organization / regulation of cellular component organization / positive regulation of response to stimulus / regulation of response to drug / group II metabotropic glutamate receptor activity / adenylate cyclase inhibiting G protein-coupled glutamate receptor activity / regulation of cellular response to stress / macrolide binding / TORC2 complex ...adenylate cyclase-inhibiting G protein-coupled glutamate receptor signaling pathway / cellular component organization / regulation of cellular component organization / positive regulation of response to stimulus / regulation of response to drug / group II metabotropic glutamate receptor activity / adenylate cyclase inhibiting G protein-coupled glutamate receptor activity / regulation of cellular response to stress / macrolide binding / TORC2 complex / activin receptor binding / TORC1 complex / cytoplasmic side of membrane / behavioral response to nicotine / intracellular glutamate homeostasis / signaling receptor inhibitor activity / transforming growth factor beta receptor binding / TGFBR1 LBD Mutants in Cancer / type I transforming growth factor beta receptor binding / negative regulation of adenylate cyclase activity / G protein-coupled glutamate receptor signaling pathway / astrocyte projection / neurotransmitter secretion / negative regulation of activin receptor signaling pathway / Class C/3 (Metabotropic glutamate/pheromone receptors) / heart trabecula formation / glutamate secretion / terminal cisterna / ryanodine receptor complex / I-SMAD binding / glutamate receptor activity / regulation of glutamate secretion / regulation of amyloid precursor protein catabolic process / long-term synaptic depression / protein maturation by protein folding / ventricular cardiac muscle tissue morphogenesis / 'de novo' protein folding / negative regulation of phosphoprotein phosphatase activity / negative regulation of macroautophagy / FK506 binding / regulation of dopamine secretion / mTORC1-mediated signalling / TGF-beta receptor signaling activates SMADs / Calcineurin activates NFAT / calcium channel regulator activity / regulation of immune response / TOR signaling / protein peptidyl-prolyl isomerization / regulation of neuron apoptotic process / heart morphogenesis / supramolecular fiber organization / regulation of ryanodine-sensitive calcium-release channel activity / regulation of synaptic transmission, glutamatergic / sarcoplasmic reticulum membrane / T cell activation / positive regulation of protein metabolic process / presynaptic modulation of chemical synaptic transmission / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / response to cocaine / peptidylprolyl isomerase / sarcoplasmic reticulum / peptidyl-prolyl cis-trans isomerase activity / G protein-coupled receptor activity / calcium ion transmembrane transport / negative regulation of transforming growth factor beta receptor signaling pathway / Sensory perception of sweet, bitter, and umami (glutamate) taste / Z disc / SARS-CoV-1 activates/modulates innate immune responses / regulation of protein localization / protein folding / presynapse / positive regulation of protein binding / presynaptic membrane / gene expression / G alpha (i) signalling events / cytoplasmic vesicle / protein refolding / scaffold protein binding / chemical synaptic transmission / positive regulation of canonical NF-kappaB signal transduction / transmembrane transporter binding / amyloid fibril formation / Potential therapeutics for SARS / positive regulation of MAPK cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / non-specific serine/threonine protein kinase / phosphorylation / axon / protein serine/threonine kinase activity / glutamatergic synapse / dendrite / protein-containing complex binding / ATP binding / membrane / nucleus / plasma membrane / cytoplasm / cytosol 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: 2.9 Å | |||||||||
データ登録者 | Wang X / Wang M / Xu T / Feng Y / Han S / Lin S / Zhao Q / Wu B | |||||||||
資金援助 | 中国, 2件
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引用 | ジャーナル: Cell Res / 年: 2023 タイトル: Structural insights into dimerization and activation of the mGlu2-mGlu3 and mGlu2-mGlu4 heterodimers. 著者: Xinwei Wang / Mu Wang / Tuo Xu / Ye Feng / Qiang Shao / Shuo Han / Xiaojing Chu / Yechun Xu / Shuling Lin / Qiang Zhao / Beili Wu / 要旨: Heterodimerization of the metabotropic glutamate receptors (mGlus) has shown importance in the functional modulation of the receptors and offers potential drug targets for treating central nervous ...Heterodimerization of the metabotropic glutamate receptors (mGlus) has shown importance in the functional modulation of the receptors and offers potential drug targets for treating central nervous system diseases. However, due to a lack of molecular details of the mGlu heterodimers, understanding of the mechanisms underlying mGlu heterodimerization and activation is limited. Here we report twelve cryo-electron microscopy (cryo-EM) structures of the mGlu2-mGlu3 and mGlu2-mGlu4 heterodimers in different conformational states, including inactive, intermediate inactive, intermediate active and fully active conformations. These structures provide a full picture of conformational rearrangement of mGlu2-mGlu3 upon activation. The Venus flytrap domains undergo a sequential conformational change, while the transmembrane domains exhibit a substantial rearrangement from an inactive, symmetric dimer with diverse dimerization patterns to an active, asymmetric dimer in a conserved dimerization mode. Combined with functional data, these structures reveal that stability of the inactive conformations of the subunits and the subunit-G protein interaction pattern are determinants of asymmetric signal transduction of the heterodimers. Furthermore, a novel binding site for two mGlu4 positive allosteric modulators was observed in the asymmetric dimer interfaces of the mGlu2-mGlu4 heterodimer and mGlu4 homodimer, and may serve as a drug recognition site. These findings greatly extend our knowledge about signal transduction of the mGlus. | |||||||||
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_36175.map.gz | 168 MB | EMDBマップデータ形式 | |
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ヘッダ (付随情報) | emd-36175-v30.xml emd-36175.xml | 17.4 KB 17.4 KB | 表示 表示 | EMDBヘッダ |
画像 | emd_36175.png | 65.6 KB | ||
Filedesc metadata | emd-36175.cif.gz | 6.8 KB | ||
その他 | emd_36175_half_map_1.map.gz emd_36175_half_map_2.map.gz | 164.9 MB 164.9 MB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-36175 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-36175 | HTTPS FTP |
-検証レポート
文書・要旨 | emd_36175_validation.pdf.gz | 752.1 KB | 表示 | EMDB検証レポート |
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文書・詳細版 | emd_36175_full_validation.pdf.gz | 751.7 KB | 表示 | |
XML形式データ | emd_36175_validation.xml.gz | 15.1 KB | 表示 | |
CIF形式データ | emd_36175_validation.cif.gz | 17.8 KB | 表示 | |
アーカイブディレクトリ | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-36175 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-36175 | HTTPS FTP |
-関連構造データ
関連構造データ | 8jd4MC 8jcuC 8jcvC 8jcwC 8jcxC 8jcyC 8jczC 8jd0C 8jd1C 8jd2C 8jd3C 8jd5C 8jd6C M: このマップから作成された原子モデル C: 同じ文献を引用 (文献) |
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類似構造データ | 類似検索 - 機能・相同性F&H 検索 |
-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_36175.map.gz / 形式: CCP4 / 大きさ: 178 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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ボクセルのサイズ | X=Y=Z: 1.071 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_36175_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_36175_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 : mGlu2-mGlu4 heterodimer in presence of glutamate, JNJ-40411813, a...
全体 | 名称: mGlu2-mGlu4 heterodimer in presence of glutamate, JNJ-40411813, and ADX88178 |
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要素 |
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-超分子 #1: mGlu2-mGlu4 heterodimer in presence of glutamate, JNJ-40411813, a...
超分子 | 名称: mGlu2-mGlu4 heterodimer in presence of glutamate, JNJ-40411813, and ADX88178 タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#2 |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
-分子 #1: Metabotropic glutamate receptor 2,Peptidyl-prolyl cis-trans isome...
分子 | 名称: Metabotropic glutamate receptor 2,Peptidyl-prolyl cis-trans isomerase FKBP1A タイプ: protein_or_peptide / ID: 1 / コピー数: 1 / 光学異性体: LEVO / EC番号: peptidylprolyl isomerase |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 109.398914 KDa |
組換発現 | 生物種: mammal environmental sample (環境試料) |
配列 | 文字列: DYKDDDDGAP EGPAKKVLTL EGDLVLGGLF PVHQKGGPAE DCGPVNEHRG IQRLEAMLFA LDRINRDPHL LPGVRLGAHI LDSCSKDTH ALEQALDFVR ASLSRGADGS RHICPDGSYA THGDAPTAIT GVIGGSYSDV SIQVANLLRL FQIPQISYAS T SAKLSDKS ...文字列: DYKDDDDGAP EGPAKKVLTL EGDLVLGGLF PVHQKGGPAE DCGPVNEHRG IQRLEAMLFA LDRINRDPHL LPGVRLGAHI LDSCSKDTH ALEQALDFVR ASLSRGADGS RHICPDGSYA THGDAPTAIT GVIGGSYSDV SIQVANLLRL FQIPQISYAS T SAKLSDKS RYDYFARTVP PDFFQAKAMA EILRFFNWTY VSTVASEGDY GETGIEAFEL EARARNICVA TSEKVGRAMS RA AFEGVVR ALLQKPSARV AVLFTRSEDA RELLAASQRL NASFTWVASD GWGALESVVA GSEGAAEGAI TIELASYPIS DFA SYFQSL DPWNNSRNPW FREFWEQRFR CSFRQRDCAA HSLRAVPFEQ ESKIMFVVNA VYAMAHALHN MHRALCPNTT RLCD AMRPV NGRRLYKDFV LNVKFDAPFR PADTHNEVRF DRFGDGIGRY NIFTYLRAGS GRYRYQKVGY WAEGLTLDTS LIPWA SPSA GPLPASRCSE PCLQNEVKSV QPGEVCCWLC IPCQPYEYRL DEFTCADCGL GYWPNASLTG CFELPQEYIR WGDAWA VGP VTIACLGALA TLFVLGVFVR HNATPVVKAS GRELCYILLG GVFLCYCMTF IFIAKPSTAV CTLRRLGLGT AFSVCYS AL LTKTNRIARI FGGAREGAQR PRFISPASQV AICLALISGQ LLIVVAWLVV EAPGTGKETA PERREVVTLR CNHRDASM L GSLAYNVLLI ALCTLYAFKT RKCPENFNEA KFIGFTMYTT CIIWLAFLPI FYVTSSDYRV QTTTMCVSVS LSGSVVLGC LFAPKLHIIL FQPQKNVVSH RAPTSRFGSA AARASSSLGQ GSGSQFVPTV CNGREVVDST TSSLLEVLFQ GPGVQVETIS PGDGRTFPK RGQTCVVHYT GMLEDGKKFD SSRDRNKPFK FMLGKQEVIR GWEEGVAQMS VGQRAKLTIS PDYAYGATGH P GIIPPHAT LVFDVELLKL EFAAAHHHHH HHHHH UniProtKB: Metabotropic glutamate receptor 2, Peptidyl-prolyl cis-trans isomerase FKBP1A |
-分子 #2: Metabotropic glutamate receptor 4,Serine/threonine-protein kinase mTOR
分子 | 名称: Metabotropic glutamate receptor 4,Serine/threonine-protein kinase mTOR タイプ: protein_or_peptide / ID: 2 / コピー数: 1 / 光学異性体: LEVO / EC番号: non-specific serine/threonine protein kinase |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 114.187086 KDa |
組換発現 | 生物種: mammal environmental sample (環境試料) |
配列 | 文字列: DYKDDDDGAP WSHPQFEKGS GSWSHPQFEK KPKGHPHMNS IRIDGDITLG GLFPVHGRGS EGKPCGELKK EKGIHRLEAM LFALDRINN DPDLLPNITL GARILDTCSR DTHALEQSLT FVQALIEKDG TEVRCGSGGP PIITKPERVV GVIGASGSSV S IMVANILR ...文字列: DYKDDDDGAP WSHPQFEKGS GSWSHPQFEK KPKGHPHMNS IRIDGDITLG GLFPVHGRGS EGKPCGELKK EKGIHRLEAM LFALDRINN DPDLLPNITL GARILDTCSR DTHALEQSLT FVQALIEKDG TEVRCGSGGP PIITKPERVV GVIGASGSSV S IMVANILR LFKIPQISYA STAPDLSDNS RYDFFSRVVP SDTYQAQAMV DIVRALKWNY VSTVASEGSY GESGVEAFIQ KS REDGGVC IAQSVKIPRE PKAGEFDKII RRLLETSNAR AVIIFANEDD IRRVLEAARR ANQTGHFFWM GSDSWGSKIA PVL HLEEVA EGAVTILPKR MSVRGFDRYF SSRTLDNNRR NIWFAEFWED NFHCKLSRHA LKKGSHVKKC TNRERIGQDS AYEQ EGKVQ FVIDAVYAMG HALHAMHRDL CPGRVGLCPR MDPVDGTQLL KYIRNVNFSG IAGNPVTFNE NGDAPGRYDI YQYQL RNDS AEYKVIGSWT DHLHLRIERM HWPGSGQQLP RSICSLPCQP GERKKTVKGM PCCWHCEPCT GYQYQVDRYT CKTCPY DMR PTENRTGCRP IPIIKLEWGS PWAVLPLFLA VVGIAATLFV VITFVRYNDT PIVKASGREL SYVLLAGIFL CYATTFL MI AEPDLGTCSL RRIFLGLGMS ISYAALLTKT NRIYRIFEQG KRSVSAPRFI SPASQLAITF SLISLQLLGI CVWFVVDP S HSVVDFQDQR TLDPRFARGV LKCDISDLSL ICLLGYSMLL MVTCTVYAIK TRGVPETFNE AKPIGFTMYT TCIVWLAFI PIFFGTSQSA DKLYIQTTTL TVSVSLSASV SLGMLYMPKV YIILFHPEQN VPKRKRSLKA VVTAATMSNK FTQKGNFRPN GEAKSELCE NLEAPALATK QTYVTYTNHA ILEVLFQGPA ILWHEMWHEG LEEASRLYFG ERNVKGMFEV LEPLHAMMER G PQTLKETS FNQAYGRDLM EAQEWCRKYM KSGNVKDLTQ AWDLYYHVFR RISKQ UniProtKB: Metabotropic glutamate receptor 4, Serine/threonine-protein kinase mTOR |
-分子 #3: 2-acetamido-2-deoxy-beta-D-glucopyranose
分子 | 名称: 2-acetamido-2-deoxy-beta-D-glucopyranose / タイプ: ligand / ID: 3 / コピー数: 3 / 式: NAG |
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分子量 | 理論値: 221.208 Da |
Chemical component information | ChemComp-NAG: |
-分子 #4: GLUTAMIC ACID
分子 | 名称: GLUTAMIC ACID / タイプ: ligand / ID: 4 / コピー数: 2 / 式: GLU |
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分子量 | 理論値: 147.129 Da |
Chemical component information | ChemComp-GLU: |
-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: 7.5 |
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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 BIOQUANTUM (6k x 4k) 平均電子線量: 70.0 e/Å2 |
電子線 | 加速電圧: 300 kV / 電子線源: FIELD EMISSION GUN |
電子光学系 | 照射モード: SPOT SCAN / 撮影モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 1.5 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: INSILICO MODEL |
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最終 再構成 | 解像度のタイプ: BY AUTHOR / 解像度: 2.9 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 使用した粒子像数: 653804 |
初期 角度割当 | タイプ: MAXIMUM LIKELIHOOD |
最終 角度割当 | タイプ: MAXIMUM LIKELIHOOD |