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データを開く
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基本情報
| 登録情報 | ![]() | |||||||||
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| タイトル | Cryo-EM structure of asimadoline-BMS-986187-bound KOR-Gi1 complex | |||||||||
マップデータ | ||||||||||
試料 |
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キーワード | Complex / Agonist / MEMBRANE PROTEIN | |||||||||
| 機能・相同性 | 機能・相同性情報Adenylate cyclase inhibitory pathway / response to acrylamide / dynorphin receptor activity / regulation of saliva secretion / sensory perception of temperature stimulus / positive regulation of eating behavior / adenylate cyclase-inhibiting opioid receptor signaling pathway / negative regulation of luteinizing hormone secretion / G protein-coupled opioid receptor activity / maternal behavior ...Adenylate cyclase inhibitory pathway / response to acrylamide / dynorphin receptor activity / regulation of saliva secretion / sensory perception of temperature stimulus / positive regulation of eating behavior / adenylate cyclase-inhibiting opioid receptor signaling pathway / negative regulation of luteinizing hormone secretion / G protein-coupled opioid receptor activity / maternal behavior / G protein-coupled opioid receptor signaling pathway / positive regulation of dopamine secretion / positive regulation of potassium ion transmembrane transport / receptor serine/threonine kinase binding / positive regulation of p38MAPK cascade / neuropeptide binding / ADP signalling through P2Y purinoceptor 12 / Adrenaline,noradrenaline inhibits insulin secretion / Extra-nuclear estrogen signaling / sensory perception / eating behavior / G alpha (i) signalling events / estrous cycle / conditioned place preference / MECP2 regulates neuronal receptors and channels / behavioral response to cocaine / sensory perception of pain / positive regulation of protein localization to cell cortex / T-tubule / G protein-coupled serotonin receptor binding / locomotory behavior / axon terminus / cellular response to forskolin / regulation of mitotic spindle organization / Peptide ligand-binding receptors / electron transport chain / sarcoplasmic reticulum / response to nicotine / cellular response to glucose stimulus / neuropeptide signaling pathway / response to insulin / response to estrogen / G protein-coupled receptor binding / G-protein beta/gamma-subunit complex binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G protein-coupled acetylcholine receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / Prostacyclin signalling through prostacyclin receptor / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / GDP binding / synaptic vesicle membrane / G beta:gamma signalling through BTK / photoreceptor disc membrane / ADP signalling through P2Y purinoceptor 12 / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / 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 / ADP signalling through P2Y purinoceptor 1 / cellular response to catecholamine stimulus / G beta:gamma signalling through PI3Kgamma / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / cellular response to lipopolysaccharide / GPER1 signaling / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / G alpha (12/13) signalling events / G-protein beta-subunit binding / extracellular vesicle / Thrombin signalling through proteinase activated receptors (PARs) / signaling receptor complex adaptor activity / GTPase binding / midbody / presynaptic membrane / chemical synaptic transmission / Ca2+ pathway / cell cortex / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / defense response to virus / G alpha (i) signalling events / G alpha (s) signalling events / response to ethanol / G alpha (q) 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 類似検索 - 分子機能 | |||||||||
| 生物種 | Homo sapiens (ヒト) / Oplophorus gracilirostris (節足動物) / synthetic construct (人工物) | |||||||||
| 手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 2.58 Å | |||||||||
データ登録者 | Zhao C / Fu H / Tian XW / Cheng L / Shao ZH | |||||||||
| 資金援助 | 中国, 2件
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引用 | ジャーナル: Signal Transduct Target Ther / 年: 2026タイトル: Molecular mechanism of allosteric modulation of opioid receptors. 著者: Heli Wang / Zhuang Miao / Chang Zhao / Hong Fu / Xiaowen Tian / Xinlei Liu / Lei Wang / Yuan Liu / Xingyu Liu / Xihao Yong / Lantian Su / Wei Yan / Lin Cheng / Renjie Chai / Zhenhua Shao / Bowen Ke / ![]() 要旨: Opioid analgesics provide potent pain relief but are limited by severe adverse effects, tolerance, and interindividual genetic variability in response. Poly-pharmacology and allosteric modulation of ...Opioid analgesics provide potent pain relief but are limited by severe adverse effects, tolerance, and interindividual genetic variability in response. Poly-pharmacology and allosteric modulation of opioid receptors offer promising strategies to enhance analgesic efficacy while mitigating these limitations. Pan-positive allosteric modulators (pan-PAMs), which simultaneously potentiate multiple opioid receptor subtypes, integrate the advantages of both approaches and represent an emerging therapeutic paradigm for pain management. However, the molecular mechanisms underlying pan-PAM activity at opioid receptors remain poorly understood. Here, we characterize BMS-986187 as a pan-PAM of opioid receptors and report the cryo-electron microscopy (cryo-EM) structures of multiple opioid receptor subtypes bound to this modulator, revealing a previously unidentified allosteric pocket. Structural and functional analyses revealed a conserved binding motif that mediates PAM recognition across the opioid receptor family and revealed the essential contributions of key opioid receptor residues to allosteric modulation by BMS-986187. Functionally, BMS-986187 enhances analgesic efficacy through an opioid-sparing effect, allowing lower opioid doses and reducing side effects, while restoring activity in loss-of-function (LOF) μ-opioid receptor variants. These findings define a previously unrecognized allosteric site in opioid receptors and establish a structural framework for the rational design of safer and more effective opioid therapeutics through allosteric modulation. | |||||||||
| 履歴 |
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構造の表示
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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_66773.map.gz | 96.7 MB | EMDBマップデータ形式 | |
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| ヘッダ (付随情報) | emd-66773-v30.xml emd-66773.xml | 18.1 KB 18.1 KB | 表示 表示 | EMDBヘッダ |
| 画像 | emd_66773.png | 53.5 KB | ||
| Filedesc metadata | emd-66773.cif.gz | 7 KB | ||
| アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-66773 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-66773 | HTTPS FTP |
-関連構造データ
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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 |
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マップ
| ファイル | ダウンロード / ファイル: emd_66773.map.gz / 形式: CCP4 / 大きさ: 103 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: 0.76 Å | ||||||||||||||||||||||||||||||||||||
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| 対称性 | 空間群: 1 | ||||||||||||||||||||||||||||||||||||
| 詳細 | EMDB XML:
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-添付データ
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試料の構成要素
-全体 : MOR in complex with Gi heterotrimer
| 全体 | 名称: MOR in complex with Gi heterotrimer |
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| 要素 |
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-超分子 #1: MOR in complex with Gi heterotrimer
| 超分子 | 名称: MOR in complex with Gi heterotrimer / タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#4 |
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| 由来(天然) | 生物種: Homo sapiens (ヒト) |
-分子 #1: 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: 1 / 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: Oplophorus gracilirostris (節足動物) |
| 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 #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: 41.729582 KDa |
| 組換発現 | 生物種: ![]() |
| 配列 | 文字列: MHHHHHHLEV LFQGPGSSGS ELDQLRQEAE QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLV SASQDGKLII WDSYTTNKVH AIPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG H TGYLSCCR ...文字列: MHHHHHHLEV LFQGPGSSGS ELDQLRQEAE QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLV SASQDGKLII WDSYTTNKVH AIPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG H TGYLSCCR FLDDNQIVTS SGDTTCALWD IETGQQTTTF TGHTGDVMSL SLAPDTRLFV SGACDASAKL WDVREGMCRQ TF TGHESDI NAICFFPNGN AFATGSDDAT CRLFDLRADQ ELMTYSHDNI ICGITSVSFS KSGRLLLAGY DDFNCNVWDA LKA DRAGVL AGHDNRVSCL GVTDDGMAVA TGSWDSFLKI WNGGSGGGGS GGSSSGGVSG WRLFKKIS UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 |
-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: Homo sapiens (ヒト) |
| 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: Soluble cytochrome b562,Kappa-type opioid receptor,Soluble cytoch...
| 分子 | 名称: Soluble cytochrome b562,Kappa-type opioid receptor,Soluble cytochrome b562,Kappa-type opioid receptor,Oplophorus-luciferin 2-monooxygenase catalytic subunit 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: synthetic construct (人工物) |
| 分子量 | 理論値: 67.793484 KDa |
| 組換発現 | 生物種: ![]() |
| 配列 | 文字列: MKTIIALSYI FCLVFADYKD DDDAADLEDN WETLNDNLKV IEKADNAAQV KDALTKMRAA ALDAQKATPP KLEDKSPDSP EMKDFRHGF DILVGQIDDA LKLANEGKVK EAQAAAEQLK TTRNAYIQKY LISPAIPVII TAVYSVVFVV GLVGNSLVMF V IIRYTKMK ...文字列: MKTIIALSYI FCLVFADYKD DDDAADLEDN WETLNDNLKV IEKADNAAQV KDALTKMRAA ALDAQKATPP KLEDKSPDSP EMKDFRHGF DILVGQIDDA LKLANEGKVK EAQAAAEQLK TTRNAYIQKY LISPAIPVII TAVYSVVFVV GLVGNSLVMF V IIRYTKMK TATNIYIFNL ALADALVTTT MPFQSTVYLM NSWPFGDVLC KIVISIDYYN MFTSIFTLTM MSVDRYIAVC HP VKALDFR TPLKAKIINI CIWLLSSSVG ISAIVLGGTK VREDVDVIEC SLQFPDDDYS WWDLFMKICV FIFAFVIPVL III VCYTLM ILRLKSVRLL SGSREKDRNL RRITRLVLVV VAVFVVCWTP IHIFILVEAL GSTSHSTAAL SSYYFCIALG YTNS SLNPI LYAFLDENFK RCFRDFCFPL KMRMERQSTS GGSGGGGSGG SSSGGVFTLE DFVGDWEQTA AYNLDQVLEQ GGVSS LLQN LAVSVTPIQR IVRSGENALK IDIHVIIPYE GLSADQMAQI EEVFKVVYPV DDHHFKVILP YGTLVIDGVT PNMLNY FGR PYEGIAVFDG KKITVTGTLW NGNKIIDERL ITPDGSMLFR VTINS UniProtKB: Soluble cytochrome b562, Kappa-type opioid receptor |
-分子 #5: Asimadoline
| 分子 | 名称: Asimadoline / タイプ: ligand / ID: 5 / コピー数: 1 / 式: A1E0F |
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| 分子量 | 理論値: 414.539 Da |
-分子 #6: 3,3,6,6-tetramethyl-9-[4-[(2-methylphenyl)methoxy]phenyl]-4,5,7,9...
| 分子 | 名称: 3,3,6,6-tetramethyl-9-[4-[(2-methylphenyl)methoxy]phenyl]-4,5,7,9-tetrahydro-2~{H}-xanthene-1,8-dione タイプ: ligand / ID: 6 / コピー数: 1 / 式: A1D6B |
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| 分子量 | 理論値: 470.599 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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解析 | 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 | TFS KRIOS |
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| 撮影 | フィルム・検出器のモデル: FEI FALCON IV (4k x 4k) 平均電子線量: 50.0 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: FLOOD BEAM / 撮影モード: BRIGHT FIELD / Cs: 2.7 mm 最大 デフォーカス(公称値): 1.4000000000000001 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 |
ムービー
コントローラー
万見について




キーワード
Homo sapiens (ヒト)
Oplophorus gracilirostris (節足動物)
データ登録者
中国, 2件
引用















































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Y (Row.)
X (Col.)




















解析
FIELD EMISSION GUN
