+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 8uhb | |||||||||||||||
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タイトル | Cryo-EM Structure of the Ro5256390-bound hTA1-Gs heterotrimer signaling complex | |||||||||||||||
要素 |
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キーワード | MEMBRANE PROTEIN / GPCR / Signaling Complex / Trace Amine-associated Receptor | |||||||||||||||
機能・相同性 | 機能・相同性情報 adenylate cyclase regulator activity / regulation of parathyroid hormone secretion / COPI-coated Golgi to ER transport vesicle / post-embryonic body morphogenesis / Amine ligand-binding receptors / : / response to parathyroid hormone / trace-amine receptor activity / genomic imprinting / positive regulation of cAMP-mediated signaling ...adenylate cyclase regulator activity / regulation of parathyroid hormone secretion / COPI-coated Golgi to ER transport vesicle / post-embryonic body morphogenesis / Amine ligand-binding receptors / : / response to parathyroid hormone / trace-amine receptor activity / genomic imprinting / positive regulation of cAMP-mediated signaling / sensory perception of chemical stimulus / tissue homeostasis / positive regulation of sodium ion transport / energy reserve metabolic process / endochondral ossification / positive regulation of osteoclast differentiation / embryonic cranial skeleton morphogenesis / : / beta2-adrenergic receptor activity / positive regulation of mini excitatory postsynaptic potential / embryonic hindlimb morphogenesis / cartilage development / positive regulation of cAMP-dependent protein kinase activity / norepinephrine binding / alkylglycerophosphoethanolamine phosphodiesterase activity / Adrenoceptors / heat generation / positive regulation of autophagosome maturation / positive regulation of AMPA receptor activity / norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure / activation of transmembrane receptor protein tyrosine kinase activity / negative regulation of smooth muscle contraction / positive regulation of lipophagy / skin development / response to psychosocial stress / negative regulation of multicellular organism growth / adrenergic receptor signaling pathway / endosome to lysosome transport / cellular response to glucagon stimulus / diet induced thermogenesis / neuronal dense core vesicle / positive regulation of protein kinase A signaling / hair follicle placode formation / adenylate cyclase binding / smooth muscle contraction / alpha-tubulin binding / mu-type opioid receptor binding / developmental growth / corticotropin-releasing hormone receptor 1 binding / G-protein alpha-subunit binding / regulation of signal transduction / D1 dopamine receptor binding / potassium channel regulator activity / positive regulation of bone mineralization / positive regulation of osteoblast differentiation / brown fat cell differentiation / beta-2 adrenergic receptor binding / adenylate cyclase-activating adrenergic receptor signaling pathway / regulation of sodium ion transport / bone resorption / ruffle / activation of adenylate cyclase activity / adenylate cyclase activator activity / negative regulation of blood pressure / response to cold / receptor-mediated endocytosis / post-embryonic development / G protein activity / positive regulation of GTPase activity / trans-Golgi network membrane / skeletal system development / G protein-coupled receptor activity / electron transport chain / ionotropic glutamate receptor binding / insulin-like growth factor receptor binding / clathrin-coated endocytic vesicle membrane / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / bone development / Activation of the phototransduction cascade / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / positive regulation of protein serine/threonine kinase activity / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / multicellular organism growth / G-protein activation / adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of insulin secretion / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / recycling endosome / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / cognition / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) 類似検索 - 分子機能 | |||||||||||||||
生物種 | Homo sapiens (ヒト) Rattus norvegicus (ドブネズミ) Lama glama (ラマ) | |||||||||||||||
手法 | 電子顕微鏡法 / 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.35 Å | |||||||||||||||
データ登録者 | Zilberg, G. / Warren, A.L. / Parpounas, A.K. / Wacker, D. | |||||||||||||||
資金援助 | 米国, 4件
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引用 | ジャーナル: Nat Commun / 年: 2024 タイトル: Molecular basis of human trace amine-associated receptor 1 activation. 著者: Gregory Zilberg / Alexandra K Parpounas / Audrey L Warren / Shifan Yang / Daniel Wacker / 要旨: The human trace amine-associated receptor 1 (hTAAR1, hTA1) is a key regulator of monoaminergic neurotransmission and the actions of psychostimulants. Despite preclinical research demonstrating its ...The human trace amine-associated receptor 1 (hTAAR1, hTA1) is a key regulator of monoaminergic neurotransmission and the actions of psychostimulants. Despite preclinical research demonstrating its tractability as a drug target, its molecular mechanisms of activation remain unclear. Moreover, poorly understood pharmacological differences between rodent and human TA1 complicate the translation of findings from preclinical disease models into novel pharmacotherapies. To elucidate hTA1's mechanisms on the molecular scale and investigate the underpinnings of its divergent pharmacology from rodent orthologs, we herein report the structure of the human TA1 receptor in complex with a Gαs heterotrimer. Our structure reveals shared structural elements with other TAARs, as well as with its closest monoaminergic orthologue, the serotonin receptor 5-HT4R. We further find that a single mutation dramatically shifts the selectivity of hTA1 towards that of its rodent orthologues, and report on the effects of substituting residues to those found in serotonin and dopamine receptors. Strikingly, we also discover that the atypical antipsychotic medication and pan-monoaminergic antagonist asenapine potently and efficaciously activates hTA1. Together our studies provide detailed insight into hTA1 structure and function, contrast its molecular pharmacology with that of related receptors, and uncover off-target activities of monoaminergic drugs at hTA1. | |||||||||||||||
履歴 |
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-構造の表示
構造ビューア | 分子: MolmilJmol/JSmol |
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-ダウンロードとリンク
-ダウンロード
PDBx/mmCIF形式 | 8uhb.cif.gz | 364 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb8uhb.ent.gz | 291.4 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 8uhb.json.gz | ツリー表示 | PDBx/mmJSON形式 | |
その他 | その他のダウンロード |
-検証レポート
文書・要旨 | 8uhb_validation.pdf.gz | 1.1 MB | 表示 | wwPDB検証レポート |
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文書・詳細版 | 8uhb_full_validation.pdf.gz | 1.1 MB | 表示 | |
XML形式データ | 8uhb_validation.xml.gz | 40.2 KB | 表示 | |
CIF形式データ | 8uhb_validation.cif.gz | 59.2 KB | 表示 | |
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/uh/8uhb ftp://data.pdbj.org/pub/pdb/validation_reports/uh/8uhb | HTTPS FTP |
-関連構造データ
関連構造データ | 42268MC M: このデータのモデリングに利用したマップデータ 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
-集合体
登録構造単位 |
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1 |
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-要素
-Guanine nucleotide-binding protein ... , 3種, 3分子 BCG
#2: タンパク質 | 分子量: 39418.086 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: GNB1 / 細胞株 (発現宿主): Sf9 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 参照: UniProt: P62873 |
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#3: タンパク質 | 分子量: 45803.598 Da / 分子数: 1 変異: E189D, M191V, T193S, E194D, N271K, K274D, R280K, T284D, I285T, G226A, A366S 由来タイプ: 組換発現 / 由来: (組換発現) Rattus norvegicus (ドブネズミ) / 遺伝子: Gnas / 細胞株 (発現宿主): Sf9 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 参照: UniProt: P63095 |
#4: タンパク質 | 分子量: 7861.143 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: GNG2 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 参照: UniProt: P59768 |
-タンパク質 / 抗体 / 非ポリマー , 3種, 3分子 AN
#1: タンパク質 | 分子量: 60019.816 Da / 分子数: 1 / 変異: M(-129)W, R(-14)G, Q(-3)E, F112W / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: cybC, ADRB2, TAAR1 / 細胞株 (発現宿主): Sf9 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 参照: UniProt: P0ABE7, UniProt: P07550, UniProt: Q96RJ0 |
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#5: 抗体 | 分子量: 14714.320 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Lama glama (ラマ) 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) |
#6: 化合物 | ChemComp-WV8 / ( |
-詳細
研究の焦点であるリガンドがあるか | Y |
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-実験情報
-実験
実験 | 手法: 電子顕微鏡法 |
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EM実験 | 試料の集合状態: PARTICLE / 3次元再構成法: 単粒子再構成法 |
-試料調製
構成要素 | 名称: hTA1-Gs-Nb35 complex (Ro5256390) / タイプ: COMPLEX / Entity ID: #1-#5 / 由来: RECOMBINANT |
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分子量 | 単位: MEGADALTONS / 実験値: NO |
由来(天然) | 生物種: Homo sapiens (ヒト) |
由来(組換発現) | 生物種: Spodoptera frugiperda (ツマジロクサヨトウ) 株: Sf9 |
緩衝液 | pH: 7.4 |
試料 | 濃度: 1.2 mg/ml / 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES |
試料支持 | グリッドの材料: COPPER / グリッドのサイズ: 300 divisions/in. / グリッドのタイプ: Quantifoil R1.2/1.3 |
急速凍結 | 装置: LEICA EM GP / 凍結剤: ETHANE |
-電子顕微鏡撮影
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |
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顕微鏡 | モデル: FEI TITAN KRIOS |
電子銃 | 電子線源: FIELD EMISSION GUN / 加速電圧: 300 kV / 照射モード: FLOOD BEAM |
電子レンズ | モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 1800 nm / 最小 デフォーカス(公称値): 500 nm |
撮影 | 電子線照射量: 53.88 e/Å2 フィルム・検出器のモデル: GATAN K3 BIOQUANTUM (6k x 4k) |
-解析
CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
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3次元再構成 | 解像度: 3.35 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 626370 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
拘束条件 |
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