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基本情報
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タイトル | CryoEM structure of delta opioid receptor bound to G proteins and a partial agonist | |||||||||
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![]() | GPCR / Delta OPIOID Receptor / bitopic ligand / MEMBRANE PROTEIN | |||||||||
機能・相同性 | ![]() G protein-coupled enkephalin receptor activity / spine apparatus / G protein-coupled opioid receptor activity / G protein-coupled opioid receptor signaling pathway / receptor serine/threonine kinase binding / cellular response to toxic substance / neuropeptide binding / eating behavior / neuronal dense core vesicle / regulation of calcium ion transport ...G protein-coupled enkephalin receptor activity / spine apparatus / G protein-coupled opioid receptor activity / G protein-coupled opioid receptor signaling pathway / receptor serine/threonine kinase binding / cellular response to toxic substance / neuropeptide binding / eating behavior / neuronal dense core vesicle / regulation of calcium ion transport / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / neuropeptide signaling pathway / negative regulation of protein-containing complex assembly / 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 / adenylate cyclase regulator activity / adenylate cyclase-inhibiting serotonin receptor signaling pathway / axon terminus / dendrite membrane / cellular response to forskolin / regulation of mitotic spindle organization / Peptide ligand-binding receptors / adult locomotory behavior / regulation of mitochondrial membrane potential / response to nicotine / Regulation of insulin secretion / positive regulation of cholesterol biosynthetic process / G protein-coupled receptor binding / negative regulation of insulin secretion / postsynaptic density membrane / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / cellular response to growth factor stimulus / response to peptide hormone / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / centriolar satellite / 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 / synaptic vesicle membrane / 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 / G protein activity / presynaptic membrane / GTPase binding / Ca2+ pathway / midbody / fibroblast proliferation / cell cortex / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / response to ethanol / 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 / cellular response to hypoxia / 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 / Extra-nuclear estrogen signaling 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: 2.8 Å | |||||||||
![]() | Fay JF / Che T | |||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Structure-guided design of partial agonists at an opioid receptor. 著者: Balazs R Varga / Sarah M Bernhard / Amal El Daibani / Saheem A Zaidi / Jordy H Lam / Jhoan Aguilar / Kevin Appourchaux / Antonina L Nazarova / Alexa Kouvelis / Ryosuke Shinouchi / Haylee R ...著者: Balazs R Varga / Sarah M Bernhard / Amal El Daibani / Saheem A Zaidi / Jordy H Lam / Jhoan Aguilar / Kevin Appourchaux / Antonina L Nazarova / Alexa Kouvelis / Ryosuke Shinouchi / Haylee R Hammond / Shainnel O Eans / Violetta Weinreb / Elyssa B Margolis / Jonathan F Fay / Xi-Ping Huang / Amynah Pradhan / Vsevolod Katritch / Jay P McLaughlin / Susruta Majumdar / Tao Che / ![]() 要旨: Chronic pain and opioid overdose deaths highlight the need for non-addictive analgesics with novel mechanisms. The δ opioid receptor (δOR) is a promising target, as it lacks the respiratory ...Chronic pain and opioid overdose deaths highlight the need for non-addictive analgesics with novel mechanisms. The δ opioid receptor (δOR) is a promising target, as it lacks the respiratory depression associated with µ opioid receptor (µOR) agonists. However, early δOR full agonists caused seizures, limiting their clinical use. Partial δOR agonists may offer more controlled receptor activation than full agonists, but their development has been hindered by uncertainty regarding the molecular mechanism of partial agonism. Here we show that C6-Quino, a bitopic ligand developed through structure-based design, acts as a selective δOR partial agonist. Functional studies reveal that C6-Quino shows differential activity at G-protein and arrestin pathways and interacts with the sodium binding pocket, confirmed through cryo-EM analysis. C6-Quino demonstrates oral activity, analgesic activity in chronic pain models without causing δOR-related seizures and µOR-related adverse effects which have limited opioid usage in recent times. This discovery outlines a new strategy for developing δOR-targeted analgesics and provides a framework for optimizing signaling profiles of other Class A GPCRs. | |||||||||
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構造の表示
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-EMDBアーカイブ
マップデータ | ![]() | 78.2 MB | ![]() | |
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ヘッダ (付随情報) | ![]() ![]() | 27 KB 27 KB | 表示 表示 | ![]() |
画像 | ![]() | 122.4 KB | ||
Filedesc metadata | ![]() | 7.3 KB | ||
その他 | ![]() ![]() ![]() ![]() | 85.2 MB 85.3 MB 84.6 MB 84.6 MB | ||
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-検証レポート
文書・要旨 | ![]() | 705.7 KB | 表示 | ![]() |
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文書・詳細版 | ![]() | 705.2 KB | 表示 | |
XML形式データ | ![]() | 13 KB | 表示 | |
CIF形式データ | ![]() | 15.3 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 | ![]() 9cgjMC ![]() 9cgkC 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: 0.88 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
-追加マップ: #1
ファイル | emd_45581_additional_1.map | ||||||||||||
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投影像・断面図 |
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密度ヒストグラム |
-追加マップ: local receptor-only refinment
ファイル | emd_45581_additional_2.map | ||||||||||||
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注釈 | local receptor-only refinment | ||||||||||||
投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: #2
ファイル | emd_45581_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_45581_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 : CryoEM structure of delta opioid receptor bound to G proteins and...
全体 | 名称: CryoEM structure of delta opioid receptor bound to G proteins and a partial agonist |
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要素 |
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-超分子 #1: CryoEM structure of delta opioid receptor bound to G proteins and...
超分子 | 名称: CryoEM structure of delta opioid receptor bound to G proteins and a partial agonist 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: ![]() |
-分子 #1: Delta-type opioid receptor
分子 | 名称: Delta-type opioid receptor / 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: ![]() |
分子量 | 理論値: 33.663402 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: GSPGARSASS LALAIAITAL YSAVCAVGLL GNVLVMFGIV RYTKMKTATN IYIFNLALAD ALATSTLPFQ SAKYLMETWP FGELLCKAV LSIDYYNMFT SIFTLTMMSV DRYIAVCHPV KALDFRTPAK AKLINICIWV LASGVGVPIM VMAVTRPRDG A VVCMLQFP ...文字列: GSPGARSASS LALAIAITAL YSAVCAVGLL GNVLVMFGIV RYTKMKTATN IYIFNLALAD ALATSTLPFQ SAKYLMETWP FGELLCKAV LSIDYYNMFT SIFTLTMMSV DRYIAVCHPV KALDFRTPAK AKLINICIWV LASGVGVPIM VMAVTRPRDG A VVCMLQFP SPSWYWDTVT KICVFLFAFV VPILIITVCY GLMLLRLRSV RLLSGSKEKD RSLRRITRMV LVVVGAFVVC WA PIHIFVI VWTLVDIDRR DPLVVAALHL CIALGYANSS LNPVLYAFLD ENFKRCFRQL CRKPCG UniProtKB: Delta-type opioid receptor |
-分子 #2: ScFv16 protein
分子 | 名称: ScFv16 protein / 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: ![]() ![]() |
分子量 | 理論値: 26.679721 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 KAAA |
-分子 #3: 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: 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: 7.861143 KDa |
組換発現 | 生物種: ![]() ![]() |
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 #4: 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: 4 / コピー数: 1 / 光学異性体: LEVO EC番号: 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 |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 40.414047 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKNTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...文字列: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKNTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTTGIVETH FTFKDLHFKM FDVGAQRSER KKWIHCFEGV TAIIFCVALS DYDLVLAEDE EM NRMHASM KLFDSICNNK WFTDTSIILF LNKKDLFEEK IKKSPLTICY PEYAGSNTYE EAAAYIQCQF EDLNKRKDTK EIY THFTCS TDTKNVQFVF DAVTDVIIKN NLKDCGLF UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-1 |
-分子 #5: 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: 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: 37.342785 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: GSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL ...文字列: GSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL WDIETGQQTT TFTGHTGDVM SLSLAPDTRL FVSGACDASA KLWDVREGMC RQTFTGHESD INAICFFPNG NA FATGSDD ATCRLFDLRA DQELMTYSHD NIICGITSVS FSKSGRLLLA GYDDFNCNVW DALKADRAGV LAGHDNRVSC LGV TDDGMA VATGSWDSFL KIWN UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 |
-分子 #6: N-{6-[(4bS,8R,8aS,15bR)-1,8a-dihydroxy-5,6,8,8a,9,15b-hexahydro-7...
分子 | 名称: N-{6-[(4bS,8R,8aS,15bR)-1,8a-dihydroxy-5,6,8,8a,9,15b-hexahydro-7H-4,8-methano[1]benzofuro[3,2-c]pyrido[3,4-b]acridin-7-yl]hexyl}guanidine タイプ: ligand / ID: 6 / コピー数: 1 / 式: A1AWC |
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分子量 | 理論値: 513.631 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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凍結 | 凍結剤: ETHANE-PROPANE |
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電子顕微鏡法
顕微鏡 | FEI TALOS ARCTICA |
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撮影 | フィルム・検出器のモデル: GATAN K3 (6k x 4k) / 実像数: 4175 / 平均電子線量: 47.4 e/Å2 |
電子線 | 加速電圧: 200 kV / 電子線源: ![]() |
電子光学系 | 照射モード: FLOOD BEAM / 撮影モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 2.2 µm / 最小 デフォーカス(公称値): 0.4 µm |
実験機器 | ![]() モデル: Talos Arctica / 画像提供: FEI Company |