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基本情報
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タイトル | Kappa opioid receptor:Galphai protein in complex with inverse agonist JDTic , no scFv16 | |||||||||
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![]() | G protein coupled receptor / Opioid receptor / MEMBRANE PROTEIN | |||||||||
機能・相同性 | ![]() response to acrylamide / adenylate cyclase-inhibiting opioid receptor signaling pathway / dynorphin receptor activity / regulation of saliva secretion / negative regulation of luteinizing hormone secretion / sensory perception of temperature stimulus / positive regulation of eating behavior / G protein-coupled opioid receptor activity / G protein-coupled opioid receptor signaling pathway / positive regulation of dopamine secretion ...response to acrylamide / adenylate cyclase-inhibiting opioid receptor signaling pathway / dynorphin receptor activity / regulation of saliva secretion / negative regulation of luteinizing hormone secretion / sensory perception of temperature stimulus / positive regulation of eating behavior / G protein-coupled opioid receptor activity / G protein-coupled opioid receptor signaling pathway / positive regulation of dopamine secretion / sensory perception / positive regulation of potassium ion transmembrane transport / receptor serine/threonine kinase binding / maternal behavior / conditioned place preference / neuropeptide binding / positive regulation of p38MAPK cascade / eating behavior / behavioral response to cocaine / neuropeptide signaling pathway / positive regulation of protein localization to cell cortex / Adenylate cyclase inhibitory pathway / T cell migration / estrous cycle / MECP2 regulates neuronal receptors and channels / 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 / sensory perception of pain / T-tubule / cellular response to forskolin / regulation of mitotic spindle organization / Peptide ligand-binding receptors / sarcoplasmic reticulum / locomotory behavior / Regulation of insulin secretion / response to insulin / response to nicotine / positive regulation of cholesterol biosynthetic process / G protein-coupled receptor binding / cellular response to glucose stimulus / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / response to peptide hormone / 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 / response to estrogen / G-protein activation / synaptic vesicle membrane / 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 / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / 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) / presynaptic membrane / G protein activity / cellular response to lipopolysaccharide / GTPase binding / Ca2+ pathway / retina development in camera-type eye / midbody / cell cortex / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / fibroblast proliferation 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: 3.58 Å | |||||||||
![]() | Gati C / Motiwala Z / Tyson AS / Styrpejko D / Han GW / Khan S / Ramos-Gonzalez N / Shenvi R / Majumdar S | |||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Molecular mechanisms of inverse agonism via κ-opioid receptor-G protein complexes. 著者: Aaliyah S Tyson / Saif Khan / Zenia Motiwala / Gye Won Han / Zixin Zhang / Mohsen Ranjbar / Daniel Styrpejko / Nokomis Ramos-Gonzalez / Stone Woo / Kelly Villers / Delainey Landaker / Terry ...著者: Aaliyah S Tyson / Saif Khan / Zenia Motiwala / Gye Won Han / Zixin Zhang / Mohsen Ranjbar / Daniel Styrpejko / Nokomis Ramos-Gonzalez / Stone Woo / Kelly Villers / Delainey Landaker / Terry Kenakin / Ryan Shenvi / Susruta Majumdar / Cornelius Gati / ![]() 要旨: Opioid receptors, a subfamily of G protein-coupled receptors (GPCRs), are key therapeutic targets. In the canonical GPCR activation model, agonist binding is required for receptor-G protein complex ...Opioid receptors, a subfamily of G protein-coupled receptors (GPCRs), are key therapeutic targets. In the canonical GPCR activation model, agonist binding is required for receptor-G protein complex formation, while antagonists prevent G protein coupling. However, many GPCRs exhibit basal activity, allowing G protein association without an agonist. The pharmacological impact of agonist-free receptor-G protein complexes is poorly understood. Here we present biochemical evidence that certain κ-opioid receptor (KOR) inverse agonists can act via KOR-G protein complexes. To investigate this phenomenon, we determined cryo-EM structures of KOR-G protein complexes with three inverse agonists: JDTic, norBNI and GB18, corresponding to structures of inverse agonist-bound GPCR-G protein complexes. Remarkably, the orthosteric binding pocket resembles the G protein-free 'inactive' receptor conformation, while the receptor remains coupled to the G protein. In summary, our work challenges the canonical model of receptor antagonism and offers crucial insights into GPCR pharmacology. | |||||||||
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マップデータ | ![]() | 55.1 MB | ![]() | |
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ヘッダ (付随情報) | ![]() ![]() | 21.5 KB 21.5 KB | 表示 表示 | ![]() |
画像 | ![]() | 70.2 KB | ||
Filedesc metadata | ![]() | 7.5 KB | ||
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 | ![]() 9d61MC ![]() 8vveC ![]() 8vvfC ![]() 8vvgC ![]() 46583 ![]() 46584 ![]() 46608 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: 1.294 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
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試料の構成要素
-全体 : Kappa opioid receptor in complex with heterotrimeric G protein (G...
全体 | 名称: Kappa opioid receptor in complex with heterotrimeric G protein (Gai/b/g) and inverse agonist JDTic |
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要素 |
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-超分子 #1: Kappa opioid receptor in complex with heterotrimeric G protein (G...
超分子 | 名称: Kappa opioid receptor in complex with heterotrimeric G protein (Gai/b/g) and inverse agonist JDTic 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: ![]() |
分子量 | 理論値: 130 kDa/nm |
-分子 #1: Kappa-type opioid receptor
分子 | 名称: Kappa-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: 42.68102 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MDSPIQIFRG EPGPTCAPSA CLPPNSSAWF PGWAEPDSNG SAGSEDAQLE PAHISPAIPV IITAVYSVVF VVGLVGNSLV MFVIIRYTK MKTATNIYIF NLALADALVT TTMPFQSTVY LMNSWPFGDV LCKIVISIDY YNMFTSIFTL TMMSVDRYIA V CHPVKALD ...文字列: MDSPIQIFRG EPGPTCAPSA CLPPNSSAWF PGWAEPDSNG SAGSEDAQLE PAHISPAIPV IITAVYSVVF VVGLVGNSLV MFVIIRYTK MKTATNIYIF NLALADALVT TTMPFQSTVY LMNSWPFGDV LCKIVISIDY YNMFTSIFTL TMMSVDRYIA V CHPVKALD FRTPLKAKII NICIWLLSSS VGISAIVLGG TKVREDVDVI ECSLQFPDDD YSWWDLFMKI CVFIFAFVIP VL IIIVCYT LMILRLKSVR LLSGSREKDR NLRRITRLVL VVVAVFVVCW TPIHIFILVE ALGSTSHSTA ALSSYYFCIA LGY TNSSLN PILYAFLDEN FKRCFRDFCF PLKMRMERQS TSRVRNTVQD PAYLRDIDGM NKPV UniProtKB: Kappa-type opioid receptor |
-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: ![]() |
分子量 | 理論値: 37.41693 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL ...文字列: MSELDQLRQE 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 #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 |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 40.415031 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKSTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...文字列: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKSTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTTGIVETH FTFKDLHFKM FDVGGQRSER KKWIHCFEGV TAIIFCVALS DYDLVLAEDE EM NRMHESM KLFDSICNNK WFTDTSIILF LNKKDLFEEK IKKSPLTICY PEYAGSNTYE EAAAYIQCQF EDLNKRKDTK EIY THFTCA TDTKNVQFVF DAVTDVIIKN NLKDCGLF UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-1 |
-分子 #5: (3R)-7-hydroxy-N-{(2S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethy...
分子 | 名称: (3R)-7-hydroxy-N-{(2S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]-3-methylbutan-2-yl}-1,2,3,4-tetrahydroisoquinoline-3-carboxamide タイプ: ligand / ID: 5 / コピー数: 1 / 式: JDC |
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分子量 | 理論値: 465.628 Da |
Chemical component information | ![]() ChemComp-JDC: |
-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
濃度 | 18 mg/mL | ||||||||||||
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緩衝液 | pH: 7.5 構成要素:
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グリッド | モデル: UltrAuFoil R1.2/1.3 / 材質: GOLD / メッシュ: 200 / 支持フィルム - 材質: GOLD / 支持フィルム - トポロジー: HOLEY ARRAY / 前処理 - タイプ: GLOW DISCHARGE / 前処理 - 時間: 60 sec. | ||||||||||||
凍結 | 凍結剤: ETHANE / チャンバー内湿度: 90 % / チャンバー内温度: 298 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 Bioquantum / エネルギーフィルター - スリット幅: 20 eV |
撮影 | フィルム・検出器のモデル: GATAN K3 BIOQUANTUM (6k x 4k) 撮影したグリッド数: 1 / 平均電子線量: 60.0 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 / 倍率(補正後): 105000 / 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): -25.0 µm / 最小 デフォーカス(公称値): -15.0 µm |
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 |