+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 8jlp | ||||||
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タイトル | Ralmitaront(RO-6889450)-bound hTAAR1-Gs protein complex | ||||||
要素 |
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キーワード | MEMBRANE PROTEIN / Complex / Agonist | ||||||
機能・相同性 | 機能・相同性情報 Amine ligand-binding receptors / trace-amine receptor activity / G protein-coupled receptor activity / electron transport chain / Olfactory Signaling Pathway / Activation of the phototransduction cascade / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor ...Amine ligand-binding receptors / trace-amine receptor activity / G protein-coupled receptor activity / electron transport chain / Olfactory Signaling Pathway / Activation of the phototransduction cascade / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Glucagon signaling in metabolic regulation / 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 / G beta:gamma signalling through CDC42 / Vasopressin regulates renal water homeostasis via Aquaporins / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / G alpha (z) signalling events / Adrenaline,noradrenaline inhibits insulin secretion / 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 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / GPER1 signaling / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / cellular response to prostaglandin E stimulus / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / 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 / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / periplasmic space / electron transfer activity / iron ion binding / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / heme binding / synapse / protein-containing complex binding / signal transduction / extracellular exosome / membrane / plasma membrane / cytosol / cytoplasm 類似検索 - 分子機能 | ||||||
生物種 | Homo sapiens (ヒト) Escherichia coli (大腸菌) | ||||||
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: 3.23 Å | ||||||
データ登録者 | Xu, Z. / Guo, L.L. / Zhao, C. / Shen, S.Y. / Sun, J.P. / Shao, Z.H. | ||||||
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
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 | 8jlp.cif.gz | 184 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb8jlp.ent.gz | 137.7 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 8jlp.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 | 8jlp_validation.pdf.gz | 1.3 MB | 表示 | wwPDB検証レポート |
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文書・詳細版 | 8jlp_full_validation.pdf.gz | 1.3 MB | 表示 | |
XML形式データ | 8jlp_validation.xml.gz | 37.1 KB | 表示 | |
CIF形式データ | 8jlp_validation.cif.gz | 54.1 KB | 表示 | |
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/jl/8jlp ftp://data.pdbj.org/pub/pdb/validation_reports/jl/8jlp | HTTPS FTP |
-関連構造データ
関連構造データ | 36403MC 8jljC 8jlkC 8jlnC 8jloC 8jlqC 8jlrC 8jsoC 8jspC 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
#1: タンパク質 | 分子量: 43117.918 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) |
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#2: タンパク質 | 分子量: 39141.793 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 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 参照: UniProt: P62873 |
#3: タンパク質 | 分子量: 54128.133 Da / 分子数: 1 / Mutation: M29W,H124I,R128L / 由来タイプ: 組換発現 由来: (組換発現) Escherichia coli (大腸菌), (組換発現) Homo sapiens (ヒト) 遺伝子: cybC, TAAR1, TA1, TAR1, TRAR1 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 参照: UniProt: P0ABE7, UniProt: Q96RJ0 |
#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 |
#5: 化合物 | ChemComp-UJU / |
研究の焦点であるリガンドがあるか | Y |
-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 |
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由来(天然) |
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由来(組換発現) |
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緩衝液 | pH: 7.5 | ||||||||||||||||||||||||
試料 | 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES | ||||||||||||||||||||||||
急速凍結 | 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): 1000 nm / Cs: 2.7 mm |
撮影 | 電子線照射量: 57 e/Å2 フィルム・検出器のモデル: GATAN K2 SUMMIT (4k 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: 3.23 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 3205589 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
拘束条件 |
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