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基本情報
登録情報 | ![]() | ||||||||||||||||||
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タイトル | Buspirone-bound serotonin 1A (5-HT1A) receptor-Gi1 protein complex | ||||||||||||||||||
![]() | Buspirone-bound serotonin 1A (5-HT1A) receptor-Gi1 protein complex | ||||||||||||||||||
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![]() | GPCR Signaling Complex / Serotonin Receptor / SIGNALING PROTEIN | ||||||||||||||||||
機能・相同性 | ![]() regulation of serotonin secretion / adenylate cyclase-inhibiting serotonin receptor signaling pathway / regulation of hormone secretion / regulation of behavior / Serotonin receptors / receptor-receptor interaction / serotonin receptor signaling pathway / regulation of dopamine metabolic process / serotonin metabolic process / serotonin binding ...regulation of serotonin secretion / adenylate cyclase-inhibiting serotonin receptor signaling pathway / regulation of hormone secretion / regulation of behavior / Serotonin receptors / receptor-receptor interaction / serotonin receptor signaling pathway / regulation of dopamine metabolic process / serotonin metabolic process / serotonin binding / G protein-coupled serotonin receptor activity / gamma-aminobutyric acid signaling pathway / exploration behavior / neurotransmitter receptor activity / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / regulation of vasoconstriction / Adenylate cyclase inhibitory pathway / behavioral fear response / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / regulation of mitotic spindle organization / cellular response to forskolin / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Regulation of insulin secretion / G protein-coupled receptor binding / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / 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 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / response to peptide hormone / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / GDP binding / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / cell cortex / midbody / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / chemical synaptic transmission / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / G protein-coupled receptor signaling pathway / cell division / lysosomal membrane / GTPase activity / centrosome / synapse / dendrite / positive regulation of cell population proliferation / protein-containing complex binding / nucleolus / GTP binding / magnesium ion binding / signal transduction / extracellular exosome / nucleoplasm / membrane / plasma membrane 類似検索 - 分子機能 | ||||||||||||||||||
生物種 | Escherichia coli, Homo sapiens / ![]() | ||||||||||||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 2.62 Å | ||||||||||||||||||
![]() | Warren AL / Zilberg G / Capper MJ / Wacker D | ||||||||||||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Structural pharmacology and therapeutic potential of 5-methoxytryptamines. 著者: Audrey L Warren / David Lankri / Michael J Cunningham / Inis C Serrano / Lyonna F Parise / Andrew C Kruegel / Priscilla Duggan / Gregory Zilberg / Michael J Capper / Vaclav Havel / Scott J ...著者: Audrey L Warren / David Lankri / Michael J Cunningham / Inis C Serrano / Lyonna F Parise / Andrew C Kruegel / Priscilla Duggan / Gregory Zilberg / Michael J Capper / Vaclav Havel / Scott J Russo / Dalibor Sames / Daniel Wacker / ![]() 要旨: Psychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin show potential for the treatment of various neuropsychiatric disorders. These compounds are thought to mediate their ...Psychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin show potential for the treatment of various neuropsychiatric disorders. These compounds are thought to mediate their hallucinogenic and therapeutic effects through the serotonin (5-hydroxytryptamine (5-HT)) receptor 5-HT (ref. ). However, 5-HT also plays a part in the behavioural effects of tryptamine hallucinogens, particularly 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a psychedelic found in the toxin of Colorado River toads. Although 5-HT is a validated therapeutic target, little is known about how psychedelics engage 5-HT and which effects are mediated by this receptor. Here we map the molecular underpinnings of 5-MeO-DMT pharmacology through five cryogenic electron microscopy (cryo-EM) structures of 5-HT, systematic medicinal chemistry, receptor mutagenesis and mouse behaviour. Structure-activity relationship analyses of 5-methoxytryptamines at both 5-HT and 5-HT enable the characterization of molecular determinants of 5-HT signalling potency, efficacy and selectivity. Moreover, we contrast the structural interactions and in vitro pharmacology of 5-MeO-DMT and analogues to the pan-serotonergic agonist LSD and clinically used 5-HT agonists. We show that a 5-HT-selective 5-MeO-DMT analogue is devoid of hallucinogenic-like effects while retaining anxiolytic-like and antidepressant-like activity in socially defeated animals. Our studies uncover molecular aspects of 5-HT-targeted psychedelics and therapeutics, which may facilitate the future development of new medications for neuropsychiatric disorders. | ||||||||||||||||||
履歴 |
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構造の表示
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マップデータ | ![]() | 70.1 MB | ![]() | |
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ヘッダ (付随情報) | ![]() ![]() | 24.2 KB 24.2 KB | 表示 表示 | ![]() |
FSC (解像度算出) | ![]() | 11 KB | 表示 | ![]() |
画像 | ![]() | 37.9 KB | ||
Filedesc metadata | ![]() | 7.7 KB | ||
その他 | ![]() ![]() | 134.2 MB 134.2 MB | ||
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-関連構造データ
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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 | Buspirone-bound serotonin 1A (5-HT1A) receptor-Gi1 protein complex | ||||||||||||||||||||
ボクセルのサイズ | X=Y=Z: 0.82 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
-ハーフマップ: Half Map 1
ファイル | emd_29599_half_map_1.map | ||||||||||||
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注釈 | Half Map 1 | ||||||||||||
投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: Half Map 2
ファイル | emd_29599_half_map_2.map | ||||||||||||
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注釈 | Half Map 2 | ||||||||||||
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 : Serotonin 1A (5-HT1A) receptor-Gi1 protein complex
全体 | 名称: Serotonin 1A (5-HT1A) receptor-Gi1 protein complex |
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要素 |
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-超分子 #1: Serotonin 1A (5-HT1A) receptor-Gi1 protein complex
超分子 | 名称: Serotonin 1A (5-HT1A) receptor-Gi1 protein complex / タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#4 詳細: Serotonin 1A (5-HT1A) receptor-Gi1 protein complex with components purified separately and assembled in vitro. |
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由来(天然) | 生物種: Escherichia coli, Homo sapiens |
-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 |
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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 #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 詳細: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 with n-terminal his-tag and 3C cleavage site and GSSG linker 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: 39.418086 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: ![]() |
分子量 | 理論値: 8.506765 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI LGSAGSAGSA UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 |
-分子 #4: Soluble cytochrome b562,5-hydroxytryptamine receptor 1A,5-hydroxy...
分子 | 名称: Soluble cytochrome b562,5-hydroxytryptamine receptor 1A,5-hydroxytryptamine receptor 1A タイプ: protein_or_peptide / ID: 4 詳細: N-terminal HA signal sequence, flag-tag, his-tag, tev cleavage site followed by soluble cytochrome b562 (E. coli) and truncated 5-hydroxytryptamine receptor 1A (Homo sapiens) with a point ...詳細: N-terminal HA signal sequence, flag-tag, his-tag, tev cleavage site followed by soluble cytochrome b562 (E. coli) and truncated 5-hydroxytryptamine receptor 1A (Homo sapiens) with a point mutation at position 255 in the provided sequence. This mutation is Ballesteros-Weinstein position 3.41 of 5-HT1A where the original leucine was mutated to a tryptophan. Cytochrome b562 (cybC, UniProt P0ABE7) is both n and c-terminally truncated with two point mutations.,N-terminal HA signal sequence, flag-tag, his-tag, tev cleavage site followed by soluble cytochrome b562 (E. coli) and truncated 5-hydroxytryptamine receptor 1A (Homo sapiens) with a point mutation at position 255 in the provided sequence. This mutation is Ballesteros-Weinstein position 3.41 of 5-HT1A where the original leucine was mutated to a tryptophan. Cytochrome b562 (cybC, UniProt P0ABE7) is both n and c-terminally truncated with two point mutations. 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: 61.37593 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MKTIIALSYI FCLVFADYKD DDDAKLQTMH HHHHHHHHHE NLYFQGGTTA DLEDNWETLN DNLKVIEKAD NAAQVKDALT KMRAAALDA QKATPPKLED KSPDSPEMKD FRHGFDILVG QIDDALKLAN EGKVKEAQAA AEQLKTTRNA YIQKYLTGIS D VTVSYQVI ...文字列: MKTIIALSYI FCLVFADYKD DDDAKLQTMH HHHHHHHHHE NLYFQGGTTA DLEDNWETLN DNLKVIEKAD NAAQVKDALT KMRAAALDA QKATPPKLED KSPDSPEMKD FRHGFDILVG QIDDALKLAN EGKVKEAQAA AEQLKTTRNA YIQKYLTGIS D VTVSYQVI TSLLLGTLIF CAVLGNACVV AAIALERSLQ NVANYLIGSL AVTDLMVSVL VLPMAALYQV LNKWTLGQVT CD LFIALDV LCCTSSIWHL CAIALDRYWA ITDPIDYVNK RTPRRAAALI SLTWLIGFLI SIPPMLGWRT PEDRSDPDAC TIS KDHGYT IYSTFGAFYI PLLLMLVLYG RIFRAARFRI RKTVKKVEKT GADTRHGASP APQPKKSVNG ESGSRNWRLG VESK AGGAL CANGAVRQGD DGAALEVIEV HRVGNSKEHL PLPSEAGPTP CAPASFERKN ERNAEAKRKM ALARERKTVK TLGII MGTF ILCWLPFFIV ALVLPFCESS CHMPTLLGAI INWLGYSNSL LNPVIYAYFN KDFQNAFKKI IKCKFCRQ UniProtKB: 5-hydroxytryptamine receptor 1A |
-分子 #5: Buspirone
分子 | 名称: Buspirone / タイプ: ligand / ID: 5 / コピー数: 1 / 式: YLX |
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分子量 | 理論値: 385.503 Da |
-分子 #6: [(2R)-1-[oxidanyl-[(2R,3R,5S,6R)-2,3,5,6-tetrakis(oxidanyl)-4-pho...
分子 | 名称: [(2R)-1-[oxidanyl-[(2R,3R,5S,6R)-2,3,5,6-tetrakis(oxidanyl)-4-phosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-3-tetradecanoyloxy-propan-2-yl] (5E,8E)-hexadeca-5,8,11,14-tetraenoate タイプ: ligand / ID: 6 / コピー数: 1 / 式: J40 |
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分子量 | 理論値: 854.895 Da |
Chemical component information | ![]() ChemComp-J40: |
-分子 #7: CHOLESTEROL HEMISUCCINATE
分子 | 名称: CHOLESTEROL HEMISUCCINATE / タイプ: ligand / ID: 7 / コピー数: 2 / 式: Y01 |
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分子量 | 理論値: 486.726 Da |
Chemical component information | ![]() ChemComp-Y01: |
-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 | 24 mg/mL | ||||||||||||
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緩衝液 | pH: 7.4 構成要素:
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グリッド | モデル: Quantifoil / 材質: COPPER / メッシュ: 300 / 支持フィルム - 材質: CARBON / 支持フィルム - トポロジー: HOLEY / 前処理 - タイプ: GLOW DISCHARGE | ||||||||||||
凍結 | 凍結剤: ETHANE / 装置: LEICA EM GP 詳細: Blot force 3 for 3-5 seconds was used and subsequent grids were screened for ice thickness prior to data collection.. | ||||||||||||
詳細 | Sample was mono disperse following gel filtration. The sample was immediately concentrated for CryoEM grid preparation. |
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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) / 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 | 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): 2.5 µm / 最小 デフォーカス(公称値): 0.5 µm |
実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |