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基本情報
登録情報 | ![]() | |||||||||
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タイトル | Cryo-EM structure of Dopamine 3 Receptor:Go complex bound to bitopic FOB02-04A - Conformation A | |||||||||
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![]() | GPCR / dopamine / bitopic / receptor / MEMBRANE PROTEIN | |||||||||
機能・相同性 | ![]() musculoskeletal movement, spinal reflex action / acid secretion / dopamine neurotransmitter receptor activity, coupled via Gi/Go / response to histamine / regulation of potassium ion transport / adenylate cyclase-inhibiting dopamine receptor signaling pathway / Dopamine receptors / regulation of dopamine uptake involved in synaptic transmission / positive regulation of dopamine receptor signaling pathway / phospholipase C-activating dopamine receptor signaling pathway ...musculoskeletal movement, spinal reflex action / acid secretion / dopamine neurotransmitter receptor activity, coupled via Gi/Go / response to histamine / regulation of potassium ion transport / adenylate cyclase-inhibiting dopamine receptor signaling pathway / Dopamine receptors / regulation of dopamine uptake involved in synaptic transmission / positive regulation of dopamine receptor signaling pathway / phospholipase C-activating dopamine receptor signaling pathway / negative regulation of oligodendrocyte differentiation / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor / Sensory perception of sweet, bitter, and umami (glutamate) taste / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / G protein-coupled receptor internalization / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Ca2+ pathway / negative regulation of synaptic transmission, glutamatergic / G alpha (z) signalling events / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / vesicle docking involved in exocytosis / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / G alpha (i) signalling events / Thrombin signalling through proteinase activated receptors (PARs) / response to morphine / G protein-coupled dopamine receptor signaling pathway / photoreceptor outer segment membrane / arachidonate secretion / negative regulation of cytosolic calcium ion concentration / spectrin binding / regulation of heart contraction / parallel fiber to Purkinje cell synapse / regulation of dopamine secretion / positive regulation of cytokinesis / alkylglycerophosphoethanolamine phosphodiesterase activity / dopamine metabolic process / social behavior / behavioral response to cocaine / photoreceptor outer segment / negative regulation of protein secretion / postsynaptic modulation of chemical synaptic transmission / prepulse inhibition / negative regulation of insulin secretion / G protein-coupled serotonin receptor binding / adenylate cyclase regulator activity / adenylate cyclase-inhibiting serotonin receptor signaling pathway / negative regulation of blood pressure / muscle contraction / photoreceptor inner segment / cardiac muscle cell apoptotic process / positive regulation of mitotic nuclear division / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / bioluminescence / learning / GABA-ergic synapse / generation of precursor metabolites and energy / locomotory behavior / circadian regulation of gene expression / response to cocaine / G protein-coupled receptor activity / visual learning / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G-protein activation / intracellular calcium ion homeostasis / 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 / ADP signalling through P2Y purinoceptor 12 / Glucagon-type ligand receptors / 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 / 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 / cellular response to prostaglandin E stimulus 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 | |||||||||
![]() | Arroyo-Urea S / Garcia-Nafria J | |||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: A bitopic agonist bound to the dopamine 3 receptor reveals a selectivity site. 著者: Sandra Arroyo-Urea / Antonina L Nazarova / Ángela Carrión-Antolí / Alessandro Bonifazi / Francisco O Battiti / Jordy Homing Lam / Amy Hauck Newman / Vsevolod Katritch / Javier García-Nafría / ![]() ![]() 要旨: Although aminergic GPCRs are the target for ~25% of approved drugs, developing subtype selective drugs is a major challenge due to the high sequence conservation at their orthosteric binding site. ...Although aminergic GPCRs are the target for ~25% of approved drugs, developing subtype selective drugs is a major challenge due to the high sequence conservation at their orthosteric binding site. Bitopic ligands are covalently joined orthosteric and allosteric pharmacophores with the potential to boost receptor selectivity and improve current medications by reducing off-target side effects. However, the lack of structural information on their binding mode impedes rational design. Here we determine the cryo-EM structure of the hDR:Gαβγ complex bound to the DR selective bitopic agonist FOB02-04A. Structural, functional and computational analyses provide insights into its binding mode and point to a new TM2-ECL1-TM1 region, which requires the N-terminal ordering of TM1, as a major determinant of subtype selectivity in aminergic GPCRs. This region is underexploited in drug development, expands the established secondary binding pocket in aminergic GPCRs and could potentially be used to design novel and subtype selective drugs. | |||||||||
履歴 |
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構造の表示
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マップデータ | ![]() | 8.4 MB | ![]() | |
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ヘッダ (付随情報) | ![]() ![]() | 22.2 KB 22.2 KB | 表示 表示 | ![]() |
画像 | ![]() | 46.3 KB | ||
マスクデータ | ![]() | 125 MB | ![]() | |
Filedesc metadata | ![]() | 7.5 KB | ||
その他 | ![]() ![]() | 98.4 MB 98.5 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 | ![]() 9f33MC ![]() 9f34C 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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注釈 | sharpened final map | ||||||||||||||||||||||||||||||||||||
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: 0.84 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
-マスク #1
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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 : D3R:Go protein complex with bitopic FOB02-04A-Conformation A
全体 | 名称: D3R:Go protein complex with bitopic FOB02-04A-Conformation A |
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要素 |
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-超分子 #1: D3R:Go protein complex with bitopic FOB02-04A-Conformation A
超分子 | 名称: D3R:Go protein complex with bitopic FOB02-04A-Conformation A 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: ![]() |
分子量 | 理論値: 190 KDa |
-分子 #1: Guanine nucleotide-binding protein G(o) subunit alpha
分子 | 名称: Guanine nucleotide-binding protein G(o) subunit alpha 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: 40.0975 KDa |
組換発現 | 生物種: ![]() |
配列 | 文字列: MGCTLSAEER AALERSKAIE KNLKEDGISA AKDVKLLLLG AGESGKNTIV KQMKIIHEDG FSGEDVKQYK PVVYSNTIQS LAAIVRAMD TLGIEYGDKE RKADAKMVCD VVSRMEDTEP FSAELLSAMM RLWGDSGIQE CFNRSREYQL NDSAKYYLDS L DRIGAADY ...文字列: MGCTLSAEER AALERSKAIE KNLKEDGISA AKDVKLLLLG AGESGKNTIV KQMKIIHEDG FSGEDVKQYK PVVYSNTIQS LAAIVRAMD TLGIEYGDKE RKADAKMVCD VVSRMEDTEP FSAELLSAMM RLWGDSGIQE CFNRSREYQL NDSAKYYLDS L DRIGAADY QPTEQDILRT RVKTTGIVET HFTFKNLHFR LFDVGAQRSE RKKWIHCFED VTAIIFCVAL SGYDQVLHED ET TNRMHAS LKLFDSICNN KFFIDTSIIL FLNKKDLFGE KIKKSPLTIC FPEYTGPNTY EDAAAYIQAQ FESKNRSPNK EIY CHMTCS TDTNNIQVVF DAVTDIIIAN NLRGCGLY UniProtKB: Guanine nucleotide-binding protein G(o) subunit alpha |
-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: 39.373992 KDa |
組換発現 | 生物種: ![]() |
配列 | 文字列: MHHHHHHHHE NLYFQGSELD QLRQEAEQLK NQIRDARKAC ADATLSQITN NIDPVGRIQM RTRRTLRGHL AKIYAMHWGT DSRLLVSAS QDGKLIIWDS YTTNKVHAIP LRSSWVMTCA YAPSGNYVAC GGLDNICSIY NLKTREGNVR VSRELAGHTG Y LSCCRFLD ...文字列: MHHHHHHHHE NLYFQGSELD QLRQEAEQLK NQIRDARKAC ADATLSQITN NIDPVGRIQM RTRRTLRGHL AKIYAMHWGT DSRLLVSAS QDGKLIIWDS YTTNKVHAIP LRSSWVMTCA YAPSGNYVAC GGLDNICSIY NLKTREGNVR VSRELAGHTG Y LSCCRFLD DNQIVTSSGD TTCALWDIET GQQTTTFTGH TGDVMSLSLA PDTRLFVSGA CDASAKLWDV REGMCRQTFT GH ESDINAI CFFPNGNAFA TGSDDATCRL FDLRADQELM TYSHDNIICG ITSVSFSKSG RLLLAGYDDF NCNVWDALKA DRA GVLAGH DNRVSCLGVT DDGMAVATGS WDSFLKIWN 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: 7.845078 KDa |
組換発現 | 生物種: ![]() |
配列 | 文字列: MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFSAI L UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 |
-分子 #4: Antibody scFv16
分子 | 名称: Antibody scFv16 / 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: 28.944244 KDa |
組換発現 | 生物種: ![]() |
配列 | 文字列: MDVQLVESGG GLVQPGGSRK LSCSASGFAF SSFGMHWVRQ APEKGLEWVA YISSGSGTIY YADTVKGRFT ISRDDPKNTL FLQMTSLRS EDTAMYYCVR SIYYYGSSPF DFWGQGTTLT VSSGGGGSGG GGSGGGGSDI VMTQATSSVP VTPGESVSIS C RSSKSLLH ...文字列: MDVQLVESGG GLVQPGGSRK LSCSASGFAF SSFGMHWVRQ APEKGLEWVA YISSGSGTIY YADTVKGRFT ISRDDPKNTL FLQMTSLRS EDTAMYYCVR SIYYYGSSPF DFWGQGTTLT VSSGGGGSGG GGSGGGGSDI VMTQATSSVP VTPGESVSIS C RSSKSLLH SNGNTYLYWF LQRPGQSPQL LIYRMSNLAS GVPDRFSGSG SGTAFTLTIS RLEAEDVGVY YCMQHLEYPL TF GAGTKLE LKGSLEVLFQ GPAAAHHHHH HHH |
-分子 #5: Green fluorescent protein,D(3) dopamine receptor
分子 | 名称: Green fluorescent protein,D(3) dopamine receptor / タイプ: protein_or_peptide / ID: 5 詳細: HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R 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: 74.733945 KDa |
組換発現 | 生物種: ![]() |
配列 | 文字列: MKTIIALSYI FCLVFADYKD DDDKVSKGEE LFTGVVPILV ELDGDVNGHK FSVSGEGEGD ATYGKLTLKF ICTTGKLPVP WPTLVTTLT YGVQCFSRYP DHMKQHDFFK SAMPEGYVQE RTIFFKDDGN YKTRAEVKFE GDTLVNRIEL KGIDFKEDGN I LGHKLEYN ...文字列: MKTIIALSYI FCLVFADYKD DDDKVSKGEE LFTGVVPILV ELDGDVNGHK FSVSGEGEGD ATYGKLTLKF ICTTGKLPVP WPTLVTTLT YGVQCFSRYP DHMKQHDFFK SAMPEGYVQE RTIFFKDDGN YKTRAEVKFE GDTLVNRIEL KGIDFKEDGN I LGHKLEYN YNSHNVYIMA DKQKNGIKVN FKIRHNIEDG SVQLADHYQQ NTPIGDGPVL LPDNHYLSTQ SALSKDPNEK RD HMVLLEF VTAAGITLGM DELYKLEVLF QGPASLSQLS SHLNYTCGAE NSTGASQARP HAYYALSYCA LILAIVFGNG LVC MAVLKE RALQTTTNYL VVSLAVADLL VATLVMPWVV YLEVTGGVWN FSRICCDVFV TLDVMMCTAS IWNLCAISID RYTA VVMPV HYQHGTGQSS CRRVALMITA VWVLAFAVSC PLLFGFNTTG DPTVCSISNP DFVIYSSVVS FYLPFGVTVL VYARI YVVL KQRRRKRILT RQNSQCNSVR PGFPQQTLSP DPAHLELKRY YSICQDTALG GPGFQERGGE LKREEKTRNS LSPTIA PKL SLEVRKLSNG RLSTSLKLGP LQPRGVPLRE KKATQMVAIV LGAFIVCWLP FFLTHVLNTH CQTCHVSPEL YSATTWL GY VNSALNPVIY TTFNIEFRKA FLKILSC UniProtKB: Green fluorescent protein, D(3) dopamine receptor |
-分子 #6: N-[2-[(1R,2S)-2-[[(2S,5S)-2-(6-azanylpyridin-3-yl)-5-methyl-morph...
分子 | 名称: N-[2-[(1R,2S)-2-[[(2S,5S)-2-(6-azanylpyridin-3-yl)-5-methyl-morpholin-4-yl]methyl]cyclopropyl]ethyl]-1H-indole-2-carboxamide タイプ: ligand / ID: 6 / コピー数: 1 / 式: A1H9N |
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分子量 | 理論値: 433.546 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
濃度 | 2.8 mg/mL |
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緩衝液 | pH: 7.4 |
グリッド | モデル: Quantifoil R0.6/1 / 材質: GOLD / メッシュ: 300 / 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: 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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撮影 | フィルム・検出器のモデル: GATAN K3 (6k x 4k) / 検出モード: SUPER-RESOLUTION / 実像数: 22655 / 平均電子線量: 50.0 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 / 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): 3.0 µm / 最小 デフォーカス(公称値): 1.0 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 |
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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: OTHER |
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得られたモデル | ![]() PDB-9f33: |