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基本情報
登録情報 | ![]() | |||||||||||||||
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タイトル | Full agonist- and positive allosteric modulator-bound mu-type opioid receptor-G protein complex | |||||||||||||||
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![]() | SIGNALING PROTEIN | |||||||||||||||
機能・相同性 | ![]() Opioid Signalling / beta-endorphin receptor activity / morphine receptor activity / negative regulation of Wnt protein secretion / regulation of cellular response to stress / G protein-coupled opioid receptor signaling pathway / behavioral response to ethanol / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / negative regulation of nitric oxide biosynthetic process / sensory perception ...Opioid Signalling / beta-endorphin receptor activity / morphine receptor activity / negative regulation of Wnt protein secretion / regulation of cellular response to stress / G protein-coupled opioid receptor signaling pathway / behavioral response to ethanol / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / negative regulation of nitric oxide biosynthetic process / sensory perception / regulation of NMDA receptor activity / neuropeptide binding / GTP metabolic process / positive regulation of neurogenesis / negative regulation of cytosolic calcium ion concentration / positive regulation of macroautophagy / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / G-protein alpha-subunit binding / neuropeptide signaling pathway / voltage-gated calcium channel activity / MECP2 regulates neuronal receptors and channels / sensory perception of pain / Peptide ligand-binding receptors / G protein-coupled receptor binding / 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 / 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 / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / 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 / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / GDP binding / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / ADORA2B mediated anti-inflammatory cytokines production / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / GTPase binding / Ca2+ pathway / midbody / fibroblast proliferation / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / perikaryon / G alpha (i) signalling events / Interleukin-4 and Interleukin-13 signaling / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / Ras protein signal transduction / Extra-nuclear estrogen signaling / neuron projection / cell population proliferation / positive regulation of ERK1 and ERK2 cascade / endosome / ciliary basal body / G protein-coupled receptor signaling pathway / Golgi membrane / axon / negative regulation of cell population proliferation / lysosomal membrane / cell division / GTPase activity / synapse / dendrite / endoplasmic reticulum membrane / protein-containing complex binding / GTP binding / nucleolus 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: 3.05 Å | |||||||||||||||
![]() | Uchikubo-Kamo T / Shirouzu M / Hisano T / Imai S / Kaneko S / Shimada I | |||||||||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Structural and dynamic insights into the activation of the μ-opioid receptor by an allosteric modulator. 著者: Shun Kaneko / Shunsuke Imai / Tomomi Uchikubo-Kamo / Tamao Hisano / Nobuaki Asao / Mikako Shirouzu / Ichio Shimada / ![]() 要旨: G-protein-coupled receptors (GPCRs) play pivotal roles in various physiological processes. These receptors are activated to different extents by diverse orthosteric ligands and allosteric modulators. ...G-protein-coupled receptors (GPCRs) play pivotal roles in various physiological processes. These receptors are activated to different extents by diverse orthosteric ligands and allosteric modulators. However, the mechanisms underlying these variations in signaling activity by allosteric modulators remain largely elusive. Here, we determine the three-dimensional structure of the μ-opioid receptor (MOR), a class A GPCR, in complex with the G protein and an allosteric modulator, BMS-986122, using cryogenic electron microscopy. Our results reveal that BMS-986122 binding induces changes in the map densities corresponding to R167 and Y254, key residues in the structural motifs conserved among class A GPCRs. Nuclear magnetic resonance analyses of MOR in the absence of the G protein reveal that BMS-986122 binding enhances the formation of the interaction between R167 and Y254, thus stabilizing the fully-activated conformation, where the intracellular half of TM6 is outward-shifted to allow for interaction with the G protein. These findings illuminate that allosteric modulators like BMS-986122 can potentiate receptor activation through alterations in the conformational dynamics in the core region of GPCRs. Together, our results demonstrate the regulatory mechanisms of GPCRs, providing insights into the rational development of therapeutics targeting GPCRs. | |||||||||||||||
履歴 |
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-EMDBアーカイブ
マップデータ | ![]() | 77.5 MB | ![]() | |
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ヘッダ (付随情報) | ![]() ![]() | 23 KB 23 KB | 表示 表示 | ![]() |
FSC (解像度算出) | ![]() | 10 KB | 表示 | ![]() |
画像 | ![]() | 77.5 KB | ||
Filedesc metadata | ![]() | 7.7 KB | ||
その他 | ![]() ![]() | 65.5 MB 65.5 MB | ||
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-検証レポート
文書・要旨 | ![]() | 812.5 KB | 表示 | ![]() |
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文書・詳細版 | ![]() | 812 KB | 表示 | |
XML形式データ | ![]() | 17.4 KB | 表示 | |
CIF形式データ | ![]() | 22.9 KB | 表示 | |
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 | ![]() 8k9lMC ![]() 8k9kC 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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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: 0.829 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_36990_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_36990_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 : Full agonist- and positive allosteric modulator-bound mu-type opi...
全体 | 名称: Full agonist- and positive allosteric modulator-bound mu-type opioid receptor-G protein complex |
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要素 |
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-超分子 #1: Full agonist- and positive allosteric modulator-bound mu-type opi...
超分子 | 名称: Full agonist- and positive allosteric modulator-bound mu-type opioid receptor-G protein complex タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#6 |
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由来(天然) | 生物種: ![]() |
-分子 #1: Soluble cytochrome b562,Mu-type opioid receptor,Mu-type opioid re...
分子 | 名称: Soluble cytochrome b562,Mu-type opioid receptor,Mu-type opioid receptor タイプ: protein_or_peptide / ID: 1 詳細: N-terminal residues (M1-G63) of MOR were replaced with the thermostabilized apocytochrome b562RIL from Escherichia coli (M7W, H102I and R106L) (BRIL) protein and a linker sequence (GSPGARSAS). ...詳細: N-terminal residues (M1-G63) of MOR were replaced with the thermostabilized apocytochrome b562RIL from Escherichia coli (M7W, H102I and R106L) (BRIL) protein and a linker sequence (GSPGARSAS). C-terminal residues (Q363-P400) of MOR were truncated.,N-terminal residues (M1-G63) of MOR were replaced with the thermostabilized apocytochrome b562RIL from Escherichia coli (M7W, H102I and R106L) (BRIL) protein and a linker sequence (GSPGARSAS). C-terminal residues (Q363-P400) of MOR were truncated. コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 51.321855 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: CLVFADYKDD DDALEVLFQG PMADLEDNWE TLNDNLKVIE KADNAAQVKD ALTKMRAAAL DAQKATPPKL EDKSPDSPEM KDFRHGFDI LVGQIDDALK LANEGKVKEA QAAAEQLKTT RNAYIQKYLG GSPGARSASS PSMITAITIM ALYSIVCVVG L FGNFLVMY ...文字列: CLVFADYKDD DDALEVLFQG PMADLEDNWE TLNDNLKVIE KADNAAQVKD ALTKMRAAAL DAQKATPPKL EDKSPDSPEM KDFRHGFDI LVGQIDDALK LANEGKVKEA QAAAEQLKTT RNAYIQKYLG GSPGARSASS PSMITAITIM ALYSIVCVVG L FGNFLVMY VIVRYTKMKT ATNIYIFNLA LADALATSTL PFQSVNYLMG TWPFGTILCK IVISIDYYNM FTSIWTLCTM SV DRYIAVC HPVKALDFRT PRNAKIINVC NWILSSAIGL PVMFMATTKY RQGSIDCTLT FSHPTWYWEN LLKICVFIFA FIM PVLIIT VCYGLMILRL KSVRMLSGSK EKDRNLRRIT RMVLVVVAVF IVCWTPIHIY VIIKALVTIP ETTFQTVSWH FCIA LGYTN SCLNPVLYAF LDENFKRCFR EFCIPTSSNI EQLEVLFQGP HHHHHHHH UniProtKB: Mu-type opioid receptor |
-分子 #2: DAMGO
分子 | 名称: DAMGO / 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: synthetic construct (人工物) |
分子量 | 理論値: 513.587 Da |
配列 | 文字列: Y(DAL)G(MEA)(ETA) |
-分子 #3: G protein subunit alpha i3
分子 | 名称: G protein subunit alpha i3 / 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: ![]() ![]() |
分子量 | 理論値: 40.585137 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MGCTLSAEDK AAVERSKMID RNLREDGEKA AKEVKLLLLG AGESGKSTIV KQMKIIHEDG YSEDECKQYK VVVYSNTIQS IIAIIRAMG RLKIDFGEAA RADDARQLFV LAGSAEEGVM TPELAGVIKR LWRDGGVQAC FSRSREYQLN DSASYYLNDL D RISQSNYI ...文字列: MGCTLSAEDK AAVERSKMID RNLREDGEKA AKEVKLLLLG AGESGKSTIV KQMKIIHEDG YSEDECKQYK VVVYSNTIQS IIAIIRAMG RLKIDFGEAA RADDARQLFV LAGSAEEGVM TPELAGVIKR LWRDGGVQAC FSRSREYQLN DSASYYLNDL D RISQSNYI PTQQDVLRTR VKTTGIVETH FTFKDLYFKM FDVGGQRSER KKWIHCFEGV TAIIFCVALS DYDLVLAEDE EM NRMHESM KLFDSICNNK WFTETSIILF LNKKDLFEEK IKRSPLTICY PEYTGSNTYE EAAAYIQCQF EDLNRRKDTK EIY THFTCA TDTKNVQFVF DAVTDVIIKN NLKECGLY UniProtKB: G protein subunit alpha i3 |
-分子 #4: 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: 4 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 38.522098 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MHHHHHHHHS ELDQLRQEAE QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLVS ASQDGKLII WDSYTTNKVH AIPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG HTGYLSCCRF L DDNQIVTS ...文字列: MHHHHHHHHS ELDQLRQEAE QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLVS ASQDGKLII WDSYTTNKVH AIPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG HTGYLSCCRF L DDNQIVTS SGDTTCALWD IETGQQTTTF TGHTGDVMSL SLAPDTRLFV SGACDASAKL WDVREGMCRQ TFTGHESDIN AI CFFPNGN AFATGSDDAT CRLFDLRADQ ELMTYSHDNI ICGITSVSFS KSGRLLLAGY DDFNCNVWDA LKADRAGVLA GHD NRVSCL GVTDDGMAVA TGSWDSFLKI WN UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 |
-分子 #5: 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: 5 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 7.932222 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MAASNNTASI AQARKLVEQL KMEANIDRIK VSKAAADLMA YCEAHAKEDP LLTPVPASEN PFREKKFFCA IL UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 |
-分子 #6: scFv16
分子 | 名称: scFv16 / タイプ: protein_or_peptide / ID: 6 詳細: N-terminal (MLLVNQSHQGFNKEHTSKMVSAIVLYVLLAAAAHSAFA) and C-terminal (GPHHHHHHHH) residues are cleaved during purification and not present in the purified sample. コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: synthetic construct (人工物) |
分子量 | 理論値: 27.409588 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS ...文字列: DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS NGNTYLYWFL QRPGQSPQLL IYRMSNLASG VPDRFSGSGS GTAFTLTISR LEAEDVGVYY CMQHLEYPLT FG AGTKLEL KAAALEVLFQ |
-分子 #7: (2~{S})-2-(3-bromanyl-4-methoxy-phenyl)-3-(4-chlorophenyl)sulfony...
分子 | 名称: (2~{S})-2-(3-bromanyl-4-methoxy-phenyl)-3-(4-chlorophenyl)sulfonyl-1,3-thiazolidine タイプ: ligand / ID: 7 / コピー数: 1 / 式: VV9 |
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分子量 | 理論値: 448.782 Da |
-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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グリッド | モデル: Quantifoil R1.2/1.3 / メッシュ: 300 / 支持フィルム - 材質: CARBON / 支持フィルム - トポロジー: HOLEY / 前処理 - タイプ: GLOW DISCHARGE |
凍結 | 凍結剤: ETHANE / チャンバー内湿度: 100 % / チャンバー内温度: 277 K / 装置: FEI VITROBOT MARK IV |
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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 Quantum LS / エネルギーフィルター - スリット幅: 15 eV |
撮影 | フィルム・検出器のモデル: GATAN K3 (6k x 4k) / 平均露光時間: 2.3 sec. / 平均電子線量: 50.5 e/Å2 |
電子線 | 加速電圧: 300 kV / 電子線源: ![]() |
電子光学系 | C2レンズ絞り径: 50.0 µm / 照射モード: FLOOD BEAM / 撮影モード: BRIGHT FIELD / Cs: 2.7 mm / 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 / 倍率(公称値): 105000 |
試料ステージ | 試料ホルダーモデル: FEI TITAN KRIOS AUTOGRID HOLDER ホルダー冷却材: NITROGEN |
実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |
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画像解析
-原子モデル構築 1
精密化 | 空間: REAL / プロトコル: RIGID BODY FIT |
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得られたモデル | ![]() PDB-8k9l: |