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万見- EMDB-36626: Ulotaront(SEP-363856)-bound Serotonin 1A (5-HT1A) receptor-Gi complex -
+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-36626 | |||||||||
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タイトル | Ulotaront(SEP-363856)-bound Serotonin 1A (5-HT1A) receptor-Gi 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 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 / behavioral fear response / regulation of vasoconstriction / T cell migration / D2 dopamine receptor binding / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / G protein-coupled serotonin receptor binding / cellular response to forskolin / regulation of mitotic spindle organization / 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 / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / 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 / 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 / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / 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 / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / 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 / GDP binding / cellular response to prostaglandin E stimulus / 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 / cell cortex / phospholipase C-activating G protein-coupled receptor signaling pathway / midbody / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) 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 / chemical synaptic transmission / G alpha (q) signalling events / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / G protein-coupled receptor signaling pathway / lysosomal membrane / cell division / GTPase activity / centrosome / dendrite / positive regulation of cell population proliferation / synapse / protein-containing complex binding / GTP binding / nucleolus / magnesium ion binding / signal transduction / extracellular exosome / nucleoplasm 類似検索 - 分子機能 | |||||||||
生物種 | Homo sapiens (ヒト) / Mus musculus (ハツカネズミ) | |||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.65 Å | |||||||||
データ登録者 | Xu Z / Guo LL / Zhao C / Shen SY / Sun JP / Shao ZH | |||||||||
資金援助 | 中国, 1件
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引用 | ジャーナル: Nature / 年: 2023 タイトル: Ligand recognition and G-protein coupling of trace amine receptor TAAR1. 著者: Zheng Xu / Lulu Guo / Jingjing Yu / Siyuan Shen / Chao Wu / Weifeng Zhang / Chang Zhao / Yue Deng / Xiaowen Tian / Yuying Feng / Hanlin Hou / Lantian Su / Hongshuang Wang / Shuo Guo / Heli ...著者: Zheng Xu / Lulu Guo / Jingjing Yu / Siyuan Shen / Chao Wu / Weifeng Zhang / Chang Zhao / Yue Deng / Xiaowen Tian / Yuying Feng / Hanlin Hou / Lantian Su / Hongshuang Wang / Shuo Guo / Heli Wang / Kexin Wang / Peipei Chen / Jie Zhao / Xiaoyu Zhang / Xihao Yong / Lin Cheng / Lunxu Liu / Shengyong Yang / Fan Yang / Xiaohui Wang / Xiao Yu / Yunfei Xu / Jin-Peng Sun / Wei Yan / Zhenhua Shao / 要旨: Trace-amine-associated receptors (TAARs), a group of biogenic amine receptors, have essential roles in neurological and metabolic homeostasis. They recognize diverse endogenous trace amines and ...Trace-amine-associated receptors (TAARs), a group of biogenic amine receptors, have essential roles in neurological and metabolic homeostasis. They recognize diverse endogenous trace amines and subsequently activate a range of G-protein-subtype signalling pathways. Notably, TAAR1 has emerged as a promising therapeutic target for treating psychiatric disorders. However, the molecular mechanisms underlying its ability to recognize different ligands remain largely unclear. Here we present nine cryo-electron microscopy structures, with eight showing human and mouse TAAR1 in a complex with an array of ligands, including the endogenous 3-iodothyronamine, two antipsychotic agents, the psychoactive drug amphetamine and two identified catecholamine agonists, and one showing 5-HTR in a complex with an antipsychotic agent. These structures reveal a rigid consensus binding motif in TAAR1 that binds to endogenous trace amine stimuli and two extended binding pockets that accommodate diverse chemotypes. Combined with mutational analysis, functional assays and molecular dynamic simulations, we elucidate the structural basis of drug polypharmacology and identify the species-specific differences between human and mouse TAAR1. Our study provides insights into the mechanism of ligand recognition and G-protein selectivity by TAAR1, which may help in the discovery of ligands or therapeutic strategies for neurological and metabolic disorders. | |||||||||
履歴 |
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-構造の表示
添付画像 |
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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_36626.map.gz | 59.7 MB | EMDBマップデータ形式 | |
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ヘッダ (付随情報) | emd-36626-v30.xml emd-36626.xml | 21.5 KB 21.5 KB | 表示 表示 | EMDBヘッダ |
画像 | emd_36626.png | 60.2 KB | ||
Filedesc metadata | emd-36626.cif.gz | 6.7 KB | ||
その他 | emd_36626_half_map_1.map.gz emd_36626_half_map_2.map.gz | 59.5 MB 59.5 MB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-36626 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-36626 | HTTPS FTP |
-検証レポート
文書・要旨 | emd_36626_validation.pdf.gz | 932 KB | 表示 | EMDB検証レポート |
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文書・詳細版 | emd_36626_full_validation.pdf.gz | 931.5 KB | 表示 | |
XML形式データ | emd_36626_validation.xml.gz | 12.3 KB | 表示 | |
CIF形式データ | emd_36626_validation.cif.gz | 14.5 KB | 表示 | |
アーカイブディレクトリ | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-36626 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-36626 | HTTPS FTP |
-関連構造データ
関連構造データ | 8jspMC 8jljC 8jlkC 8jlnC 8jloC 8jlpC 8jlqC 8jlrC 8jsoC 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 (文献) |
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類似構造データ | 類似検索 - 機能・相同性F&H 検索 |
-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 |
-マップ
ファイル | ダウンロード / ファイル: emd_36626.map.gz / 形式: CCP4 / 大きさ: 64 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: 0.92 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: #2
ファイル | emd_36626_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_36626_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 |
-試料の構成要素
-全体 : hTAAR1-bound T1AM in complex with Gs heterotrimer
全体 | 名称: hTAAR1-bound T1AM in complex with Gs heterotrimer |
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要素 |
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-超分子 #1: hTAAR1-bound T1AM in complex with Gs heterotrimer
超分子 | 名称: hTAAR1-bound T1AM in complex with Gs heterotrimer / タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#2, #4-#5, #3 |
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-超分子 #2: 5HT1A in complex with Gi heterotrimer
超分子 | 名称: 5HT1A in complex with Gi heterotrimer / タイプ: complex / ID: 2 / 親要素: 1 / 含まれる分子: #1-#2, #4-#5 |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
-超分子 #3: scFv16
超分子 | 名称: scFv16 / タイプ: complex / ID: 3 / 親要素: 1 / 含まれる分子: #3 |
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由来(天然) | 生物種: Mus musculus (ハツカネズミ) |
-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: Homo sapiens (ヒト) |
分子量 | 理論値: 40.12266 KDa |
組換発現 | 生物種: Spodoptera frugiperda (ツマジロクサヨトウ) |
配列 | 文字列: TLSAEDKAAV ERSKMIDRNL REDGEKAARE VKLLLLGAGE SGKNTIVKQM KIIHEAGYSE EECKQYKAVV YSNTIQSIIA IIRAMGRLK IDFGDSARAD DARQLFVLAG AAEEGFMTAE LAGVIKRLWK DSGVQACFNR SREYQLNDSA AYYLNDLDRI A QPNYIPTQ ...文字列: TLSAEDKAAV ERSKMIDRNL REDGEKAARE VKLLLLGAGE SGKNTIVKQM KIIHEAGYSE EECKQYKAVV YSNTIQSIIA IIRAMGRLK IDFGDSARAD DARQLFVLAG AAEEGFMTAE LAGVIKRLWK DSGVQACFNR SREYQLNDSA AYYLNDLDRI A QPNYIPTQ QDVLRTRVKT TGIVETHFTF KDLHFKMFDV GAQRSERKKW IHCFEGVTAI IFCVALSDYD LVLAEDEEMN RM HASMKLF DSICNNKWFT DTSIILFLNK KDLFEEKIKK SPLTICYPEY AGSNTYEEAA AYIQCQFEDL NKRKDTKEIY THF TCSTDT KNVQFVFDAV TDVIIKNNLK DCGLF 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: 35.985395 KDa |
組換発現 | 生物種: Spodoptera frugiperda (ツマジロクサヨトウ) |
配列 | 文字列: QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLVS ASQDGKLIIW DSYTTNKVHA IPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG HTGYLSCCRF LDDNQIVTSS GDTTCALWDI E TGQQTTTF ...文字列: QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLVS ASQDGKLIIW DSYTTNKVHA IPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG HTGYLSCCRF LDDNQIVTSS GDTTCALWDI E TGQQTTTF TGHTGDVMSL SLAPDTRLFV SGACDASAKL WDVREGMCRQ TFTGHESDIN AICFFPNGNA FATGSDDATC RL FDLRADQ ELMTYSHDNI ICGITSVSFS KSGRLLLAGY DDFNCNVWDA LKADRAGVLA GHDNRVSCLG VTDDGMAVAT GSW DSFLKI WN UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 |
-分子 #3: ScFv16
分子 | 名称: ScFv16 / 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: Mus musculus (ハツカネズミ) |
分子量 | 理論値: 26.59466 KDa |
組換発現 | 生物種: Spodoptera frugiperda (ツマジロクサヨトウ) |
配列 | 文字列: VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS SGGGGSGGGG SGGGSSDIVM TQATSSVPVT PGESVSISCR S SKSLLHSN ...文字列: VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS SGGGGSGGGG SGGGSSDIVM TQATSSVPVT PGESVSISCR S SKSLLHSN GNTYLYWFLQ RPGQSPQLLI YRMSNLASGV PDRFSGSGSG TAFTLTISRL EAEDVGVYYC MQHLEYPLTF GA GTKLELK AAA |
-分子 #4: 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: 4 / 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: 4.990752 KDa |
組換発現 | 生物種: Spodoptera frugiperda (ツマジロクサヨトウ) |
配列 | 文字列: QLKMEANIDR IKVSKAAADL MAYCEAHAKE DPLLTPVPAS ENPFR UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 |
-分子 #5: 5-hydroxytryptamine receptor 1A
分子 | 名称: 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: 42.001121 KDa |
組換発現 | 生物種: Spodoptera frugiperda (ツマジロクサヨトウ) |
配列 | 文字列: YQVITSLLLG TLIFCAVLGN ACVVAAIALE RSLQNVANYL IGSLAVTDLM VSVLVLPMAA LYQVLNKWTL GQVTCDLFIA LDVLCCTSS IWHLCAIALD RYWAITDPID YVNKRTPRRA AALISLTWLI GFLISIPPML GWRTPEDRSD PDACTISKDH G YTIYSTFG ...文字列: YQVITSLLLG TLIFCAVLGN ACVVAAIALE RSLQNVANYL IGSLAVTDLM VSVLVLPMAA LYQVLNKWTL GQVTCDLFIA LDVLCCTSS IWHLCAIALD RYWAITDPID YVNKRTPRRA AALISLTWLI GFLISIPPML GWRTPEDRSD PDACTISKDH G YTIYSTFG AFYIPLLLML VLYGRIFRAA RFRIRKTVKK VEKTGADTRH GASPAPQPKK SVNGESGSRN WRLGVESKAG GA LCANGAV RQGDDGAALE VIEVHRVGNS KEHLPLPSEA GPTPCAPASF ERKNERNAEA KRKMALARER KTVKTLGIIM GTF ILCWLP FFIVALVLPF CESSCHMPTL LGAIINWLGY SNSLLNPVIY AYFNKDFQNA FKKII UniProtKB: 5-hydroxytryptamine receptor 1A |
-分子 #6: 1-[(7~{S})-5,7-dihydro-4~{H}-thieno[2,3-c]pyran-7-yl]-~{N}-methyl...
分子 | 名称: 1-[(7~{S})-5,7-dihydro-4~{H}-thieno[2,3-c]pyran-7-yl]-~{N}-methyl-methanamine タイプ: ligand / ID: 6 詳細: This is a sythentetic compound that similar with amino acid. コピー数: 1 / 式: UJL |
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分子量 | 理論値: 183.271 Da |
Chemical component information | ChemComp-UJL: |
-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 |
-試料調製
緩衝液 | pH: 7.5 |
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凍結 | 凍結剤: ETHANE |
-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: 60.0 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): 1.8 µm / 最小 デフォーカス(公称値): 1.0 µm |
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |
-画像解析
初期モデル | モデルのタイプ: NONE |
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最終 再構成 | 解像度のタイプ: BY AUTHOR / 解像度: 3.65 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 使用した粒子像数: 313570 |
初期 角度割当 | タイプ: MAXIMUM LIKELIHOOD |
最終 角度割当 | タイプ: MAXIMUM LIKELIHOOD |