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基本情報
| 登録情報 | ![]() | |||||||||
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| タイトル | Cryo-EM structure of 5-HT1AR-GoA in complex with TMU4142 | |||||||||
マップデータ | ||||||||||
試料 |
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キーワード | signal transduction / MEMBRANE PROTEIN | |||||||||
| 機能・相同性 | 機能・相同性情報regulation of serotonin secretion / Gi/o-coupled serotonin receptor activity / regulation of hormone secretion / regulation of behavior / receptor-receptor interaction / serotonin receptor activity / Serotonin receptors / G protein-coupled serotonin receptor activity / serotonin receptor signaling pathway / regulation of dopamine metabolic process ...regulation of serotonin secretion / Gi/o-coupled serotonin receptor activity / regulation of hormone secretion / regulation of behavior / receptor-receptor interaction / serotonin receptor activity / Serotonin receptors / G protein-coupled serotonin receptor activity / serotonin receptor signaling pathway / regulation of dopamine metabolic process / neurotransmitter receptor activity / mu-type opioid receptor binding / vesicle docking involved in exocytosis / corticotropin-releasing hormone receptor 1 binding / serotonin metabolic process / serotonin binding / G protein-coupled dopamine receptor signaling pathway / gamma-aminobutyric acid signaling pathway / regulation of heart contraction / parallel fiber to Purkinje cell synapse / exploration behavior / adult behavior / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / regulation of vasoconstriction / postsynaptic modulation of chemical synaptic transmission / behavioral fear response / adenylate cyclase-inhibiting serotonin receptor signaling pathway / G protein-coupled serotonin receptor binding / muscle contraction / locomotory behavior / electron transport chain / negative regulation of insulin secretion / GABA-ergic synapse / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / adenylate cyclase-inhibiting 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 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / ADORA2B mediated anti-inflammatory cytokines production / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / cellular response to prostaglandin E stimulus / heterotrimeric G-protein complex / G alpha (12/13) signalling events / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / extracellular vesicle / sensory perception of taste / Thrombin signalling through proteinase activated receptors (PARs) / signaling receptor complex adaptor activity / retina development in camera-type eye / GTPase binding / cell body / G protein activity / presynaptic membrane / fibroblast proliferation / Ca2+ pathway / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / chemical synaptic transmission / 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 / Ras protein signal transduction / periplasmic space / electron transfer activity / postsynaptic membrane / cell population proliferation / Extra-nuclear estrogen signaling / iron ion binding / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / heme binding / positive regulation of cell population proliferation 類似検索 - 分子機能 | |||||||||
| 生物種 | Homo sapiens (ヒト) / ![]() | |||||||||
| 手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 2.86 Å | |||||||||
データ登録者 | Wang C / Cao C | |||||||||
| 資金援助 | 中国, 1件
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引用 | ジャーナル: Cell / 年: 2025タイトル: Pathway-selective 5-HTR agonist as a rapid antidepressant strategy. 著者: Chunyu Wang / Nan Zhang / Yujie Shao / Tao Li / Mengna Zhang / Meng Gao / Yaqi Liang / Yumeng Wang / Tian Xue / Yiming Shi / He Chen / Can Cao / ![]() 要旨: Presynaptic 5-HTR autoreceptors predominantly signal through G protein, mediating feedback inhibition that hampers the therapeutic efficacy of conventional antidepressants. By contrast, postsynaptic ...Presynaptic 5-HTR autoreceptors predominantly signal through G protein, mediating feedback inhibition that hampers the therapeutic efficacy of conventional antidepressants. By contrast, postsynaptic heteroreceptors mainly couple to G, which promotes antidepressant responses. However, selectively activating heteroreceptors while bypassing the negative feedback induced by autoreceptors remains a significant challenge. Here, we characterized the G subtype signaling profiles of 5-HTR and determined its structures in complex with six agonists and three distinct G family proteins: G, G, and G. Combined with functional analysis, we elucidated the mechanisms underlying diverse agonist recognition modes and G subtype signaling selectivity of 5-HTR. Furthermore, we designed a pathway-selective agonist, TMU4142, which exhibits high G activity while minimizing G activation. Remarkably, TMU4142 demonstrated rapid antidepressant-like effects in a mouse model of depression. Collectively, these findings suggest that distinguishing heteroreceptors from autoreceptors based on their distinct downstream G signaling pathways could be a promising strategy to develop fast-acting antidepressants. | |||||||||
| 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_65196.map.gz | 162.5 MB | EMDBマップデータ形式 | |
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| ヘッダ (付随情報) | emd-65196-v30.xml emd-65196.xml | 25.6 KB 25.6 KB | 表示 表示 | EMDBヘッダ |
| FSC (解像度算出) | emd_65196_fsc.xml | 11.8 KB | 表示 | FSCデータファイル |
| 画像 | emd_65196.png | 46.1 KB | ||
| Filedesc metadata | emd-65196.cif.gz | 7.7 KB | ||
| その他 | emd_65196_half_map_1.map.gz emd_65196_half_map_2.map.gz | 159.9 MB 159.9 MB | ||
| アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-65196 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-65196 | HTTPS FTP |
-関連構造データ
| 関連構造データ | ![]() 9vmyMC ![]() 9vj5C ![]() 9vj6C ![]() 9vjeC ![]() 9vjfC ![]() 9vjgC ![]() 9vnfC 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 F&H 検索 |
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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_65196.map.gz / 形式: CCP4 / 大きさ: 172.1 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: 0.82 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
-ハーフマップ: #2
| ファイル | emd_65196_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_65196_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 : Cryo-EM structure of 5-HT1AR-GoA in complex with TMU4142
| 全体 | 名称: Cryo-EM structure of 5-HT1AR-GoA in complex with TMU4142 |
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| 要素 |
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-超分子 #1: Cryo-EM structure of 5-HT1AR-GoA in complex with TMU4142
| 超分子 | 名称: Cryo-EM structure of 5-HT1AR-GoA in complex with TMU4142 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: Homo sapiens (ヒト) |
| 分子量 | 理論値: 150 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 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: Homo sapiens (ヒト) |
| 分子量 | 理論値: 40.081438 KDa |
| 組換発現 | 生物種: ![]() |
| 配列 | 文字列: MGSTLSAEER AALERSKAIE KNLKEDGISA AKDVKLLLLG AGESGKNTIV KQMKIIHEDG FSGEDVKQYK PVVYSNTIQS LAAIVRAMD TLGIEYGDKE RKADAKMVCD VVSRMEDTEP FSAELLSAMM RLWGDSGIQE CFNRSREYQL NDSAKYYLDS L DRIGAADY ...文字列: MGSTLSAEER 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: Homo sapiens (ヒト) |
| 分子量 | 理論値: 39.418086 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 WN 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: ScFv16
| 分子 | 名称: 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: 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 #5: Soluble cytochrome b562,5-hydroxytryptamine receptor 1A
| 分子 | 名称: Soluble cytochrome b562,5-hydroxytryptamine receptor 1A 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: Homo sapiens (ヒト) |
| 分子量 | 理論値: 60.921188 KDa |
| 組換発現 | 生物種: ![]() |
| 配列 | 文字列: DYKDDDDAKL QTMHHHHHHH HHHENLYFQG GTTMADLEDN WETLNDNLKV IEKADNAAQV KDALTKMRAA ALDAQKATPP KLEDKSPDS PEMKDFRHGF DILVGQIDDA LKLANEGKVK EAQAAAEQLK TTRNAYIQKY LGSTLEVLFQ GPTTGISDVT V SYQVITSL ...文字列: DYKDDDDAKL QTMHHHHHHH HHHENLYFQG GTTMADLEDN WETLNDNLKV IEKADNAAQV KDALTKMRAA ALDAQKATPP KLEDKSPDS PEMKDFRHGF DILVGQIDDA LKLANEGKVK EAQAAAEQLK TTRNAYIQKY LGSTLEVLFQ GPTTGISDVT V SYQVITSL LLGTLIFCAV LGNACVVAAI ALERSLQNVA NYLIGSLAVT DLMVSVLVLP MAALYQVLNK WTLGQVTCDL FI ALDVLCC TSSIWHLCAI ALDRYWAITD PIDYVNKRTP RRAAALISLT WLIGFLISIP PMLGWRTPED RSDPDACTIS KDH GYTIYS TFGAFYIPLL LMLVLYGRIF RAARFRIRKT VKKVEKTGAD TRHGASPAPQ PKKSVNGESG SRNWRLGVES KAGG ALCAN GAVRQGDDGA ALEVIEVHRV GNSKEHLPLP SEAGPTPCAP ASFERKNERN AEAKRKMALA RERKTVKTLG IIMGT FILC WLPFFIVALV LPFCESSCHM PTLLGAIINW LGYSNSLLNP VIYAYFNKDF QNAFKKIIKC KFCRQ UniProtKB: Soluble cytochrome b562, 5-hydroxytryptamine receptor 1A |
-分子 #6: 8-[3-[[(2~{S})-3-(1~{H}-indol-4-yloxy)-2-oxidanyl-propyl]amino]pr...
| 分子 | 名称: 8-[3-[[(2~{S})-3-(1~{H}-indol-4-yloxy)-2-oxidanyl-propyl]amino]propyl]-8-azaspiro[4.5]decane-7,9-dione タイプ: ligand / ID: 6 / コピー数: 1 / 式: A1ES2 |
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| 分子量 | 理論値: 413.51 Da |
-分子 #7: CHOLESTEROL
| 分子 | 名称: CHOLESTEROL / タイプ: ligand / ID: 7 / コピー数: 2 / 式: CLR |
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| 分子量 | 理論値: 386.654 Da |
| Chemical component information | ![]() ChemComp-CLR: |
-分子 #8: (2R)-1-(heptadecanoyloxy)-3-{[(R)-hydroxy{[(1R,2R,3R,4R,5S,6R)-2,...
| 分子 | 名称: (2R)-1-(heptadecanoyloxy)-3-{[(R)-hydroxy{[(1R,2R,3R,4R,5S,6R)-2,3,5,6-tetrahydroxy-4-(phosphonooxy)cyclohexyl]oxy}phosphoryl]oxy}propan-2-yl (5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoate タイプ: ligand / ID: 8 / コピー数: 1 / 式: T7M |
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| 分子量 | 理論値: 953.081 Da |
| Chemical component information | ![]() ChemComp-T7M: |
-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
| 濃度 | 1.5 mg/mL |
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| 緩衝液 | pH: 7.5 |
| グリッド | モデル: Quantifoil R1.2/1.3 / 材質: COPPER / 支持フィルム - 材質: CARBON / 支持フィルム - トポロジー: HOLEY |
| 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 | TFS KRIOS |
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| 撮影 | フィルム・検出器のモデル: GATAN K3 (6k 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 / 最大 デフォーカス(公称値): 18.0 µm / 最小 デフォーカス(公称値): 0.6 µm |
| 実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |
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コントローラー
万見について




キーワード
Homo sapiens (ヒト)
データ登録者
中国, 1件
引用





































Z (Sec.)
Y (Row.)
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解析
FIELD EMISSION GUN


