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基本情報
登録情報 | ![]() | |||||||||
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タイトル | Cryo-EM structure of mGlu2-mGlu3 heterodimer in presence of LY341495 and NAM563 (dimerization mode I) | |||||||||
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![]() | Complex structure / mGlu2-3 heterodimer / MEMBRANE PROTEIN | |||||||||
機能・相同性 | ![]() regulation of cellular component organization / regulation of response to drug / group II metabotropic glutamate receptor activity / regulation of cellular response to stress / macrolide binding / activin receptor binding / TORC1 complex / cytoplasmic side of membrane / regulation of skeletal muscle contraction by regulation of release of sequestered calcium ion / behavioral response to nicotine ...regulation of cellular component organization / regulation of response to drug / group II metabotropic glutamate receptor activity / regulation of cellular response to stress / macrolide binding / activin receptor binding / TORC1 complex / cytoplasmic side of membrane / regulation of skeletal muscle contraction by regulation of release of sequestered calcium ion / 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 / negative regulation of activin receptor signaling pathway / Class C/3 (Metabotropic glutamate/pheromone receptors) / heart trabecula formation / terminal cisterna / ryanodine receptor complex / glutamate secretion / 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 / FK506 binding / postsynaptic modulation of chemical synaptic transmission / regulation of dopamine secretion / channel regulator activity / TGF-beta receptor signaling activates SMADs / mTORC1-mediated signalling / protein peptidyl-prolyl isomerization / Calcineurin activates NFAT / calcium channel regulator activity / regulation of ryanodine-sensitive calcium-release channel activity / regulation of immune response / heart morphogenesis / supramolecular fiber organization / regulation of synaptic transmission, glutamatergic / sarcoplasmic reticulum membrane / T cell activation / presynaptic modulation of chemical synaptic transmission / positive regulation of protein metabolic process / negative regulation of autophagy / negative regulation of transforming growth factor beta receptor signaling pathway / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / sarcoplasmic reticulum / response to cocaine / peptidylprolyl isomerase / peptidyl-prolyl cis-trans isomerase activity / G protein-coupled receptor activity / calcium ion transmembrane transport / Z disc / regulation of protein localization / SARS-CoV-1 activates/modulates innate immune responses / protein folding / positive regulation of protein binding / presynaptic membrane / positive regulation of canonical NF-kappaB signal transduction / gene expression / G alpha (i) signalling events / protein refolding / scaffold protein binding / Potential therapeutics for SARS / chemical synaptic transmission / postsynaptic membrane / transmembrane transporter binding / amyloid fibril formation / dendritic spine / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / postsynaptic density / non-specific serine/threonine protein kinase / axon / protein serine/threonine kinase activity / glutamatergic synapse / dendrite / protein-containing complex binding / ATP binding / membrane / plasma membrane / cytoplasm / cytosol 類似検索 - 分子機能 | |||||||||
生物種 | ![]() | |||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.0 Å | |||||||||
![]() | Wang X / Wang M / Xu T / Feng Y / Han S / Lin S / Zhao Q / Wu B | |||||||||
資金援助 | ![]()
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![]() | ![]() 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
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マップデータ | ![]() | 168 MB | ![]() | |
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ヘッダ (付随情報) | ![]() ![]() | 17.8 KB 17.8 KB | 表示 表示 | ![]() |
画像 | ![]() | 47.7 KB | ||
Filedesc metadata | ![]() | 6.9 KB | ||
その他 | ![]() ![]() | 165.1 MB 165 MB | ||
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-関連構造データ
関連構造データ | ![]() 8jcwMC ![]() 8jcuC ![]() 8jcvC ![]() 8jcxC ![]() 8jcyC ![]() 8jczC ![]() 8jd0C ![]() 8jd1C ![]() 8jd2C ![]() 8jd3C ![]() 8jd4C ![]() 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 ( |
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類似構造データ | 類似検索 - 機能・相同性 ![]() |
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リンク
EMDBのページ | ![]() ![]() |
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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 | ![]() | ||||||||||||||||||||
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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_36167_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_36167_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 |
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試料の構成要素
-全体 : mGlu2-3 heterodimer in presence of LY341495 and NAM563
全体 | 名称: mGlu2-3 heterodimer in presence of LY341495 and NAM563 |
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要素 |
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-超分子 #1: mGlu2-3 heterodimer in presence of LY341495 and NAM563
超分子 | 名称: mGlu2-3 heterodimer in presence of LY341495 and NAM563 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: ![]() |
-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: ![]() |
分子量 | 理論値: 109.398914 KDa |
組換発現 | 生物種: ![]() ![]() |
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 3,Serine/threonine-protein kinase mTOR
分子 | 名称: Metabotropic glutamate receptor 3,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: ![]() |
分子量 | 理論値: 112.712961 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: DYKDDDDKGA PWSHPQFEKG SGSWSHPQFE KLGDHNFLRR EIKIEGDLVL GGLFPINEKG TGTEECGRIN EDRGIQRLEA MLFAIDEIN KDDYLLPGVK LGVHILDTCS RDTYALEQSL EFVRASLTKV DEAEYMCPDG SYAIQENIPL LIAGVIGGSY S SVSIQVAN ...文字列: DYKDDDDKGA PWSHPQFEKG SGSWSHPQFE KLGDHNFLRR EIKIEGDLVL GGLFPINEKG TGTEECGRIN EDRGIQRLEA MLFAIDEIN KDDYLLPGVK LGVHILDTCS RDTYALEQSL EFVRASLTKV DEAEYMCPDG SYAIQENIPL LIAGVIGGSY S SVSIQVAN LLRLFQIPQI SYASTSAKLS DKSRYDYFAR TVPPDFYQAK AMAEILRFFN WTYVSTVASE GDYGETGIEA FE QEARLRN ICIATAEKVG RSNIRKSYDS VIRELLQKPN ARVVVLFMRS DDSRELIAAA SRANASFTWV ASDGWGAQES IIK GSEHVA YGAITLELAS QPVRQFDRYF QSLNPYNNHR NPWFRDFWEQ KFQCSLQNKR NHRRVCDKHL AIDSSNYEQE SKIM FVVNA VYAMAHALHK MQRTLCPNTT KLCDAMKILD GKKLYKDYLL KINFTAPFNP NKDADSIVKF DTFGDGMGRY NVFNF QNVG GKYSYLKVGH WAETLSLDVN SIHWSRNSVP TSQCSDPCAP NEMKNMQPGD VCCWICIPCE PYEYLADEFT CMDCGS GQW PTADLTGCYD LPEDYIRWED AWAIGPVTIA CLGFMCTCMV VTVFIKHNNT PLVKASGREL CYILLFGVGL SYCMTFF FI AKPSPVICAL RRLGLGSSFA ICYSALLTKT NCIARIFDGV KNGAQRPKFI SPSSQVFICL GLILVQIVMV SVWLILEA P GTRRYTLAEK RETVILKCNV KDSSMLISLT YDVILVILCT VYAFKTRKCP ENFNEAKFIG FTMYTTCIIW LAFLPIFYV TSSDYRVQTT TMCISVSLSG FVVLGCLFAP KVHIILFQPQ KNVVTHRLHL NRFSVSGTGT TYSQSSASTY VPTVCNGREV LDSTTSSLL EVLFQGPAIL WHEMWHEGLE EASRLYFGER NVKGMFEVLE PLHAMMERGP QTLKETSFNQ AYGRDLMEAQ E WCRKYMKS GNVKDLTQAW DLYYHVFRRI SKQEF UniProtKB: Metabotropic glutamate receptor 3, 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: 2 / 式: NAG |
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分子量 | 理論値: 221.208 Da |
Chemical component information | ![]() ChemComp-NAG: |
-分子 #4: 2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine
分子 | 名称: 2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine タイプ: ligand / ID: 4 / コピー数: 2 / 式: Z99 |
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分子量 | 理論値: 353.369 Da |
Chemical component information | ![]() ChemComp-Z99: |
-分子 #5: CHOLESTEROL
分子 | 名称: CHOLESTEROL / タイプ: ligand / ID: 5 / コピー数: 2 / 式: CLR |
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分子量 | 理論値: 386.654 Da |
Chemical component information | ![]() ChemComp-CLR: |
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
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![]() | 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 |
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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: ![]() |
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 |
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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: 3.0 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 使用した粒子像数: 516615 |
初期 角度割当 | タイプ: MAXIMUM LIKELIHOOD |
最終 角度割当 | タイプ: MAXIMUM LIKELIHOOD |