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基本情報
登録情報 | データベース: PDB / ID: 7w6p | ||||||
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タイトル | Cryo-EM structure of the alpha2A adrenergic receptor GoA signaling complex bound to a G protein biased agonist | ||||||
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![]() | MEMBRANE PROTEIN / GPCR / G-protein / signaling complex / biased agonist | ||||||
機能・相同性 | ![]() negative regulation of uterine smooth muscle contraction / adenylate cyclase-inhibiting adrenergic receptor signaling pathway / phospholipase C-activating adrenergic receptor signaling pathway / alpha2-adrenergic receptor activity / Adrenaline signalling through Alpha-2 adrenergic receptor / alpha-2C adrenergic receptor binding / receptor transactivation / epinephrine binding / alpha-1B adrenergic receptor binding / negative regulation of norepinephrine secretion ...negative regulation of uterine smooth muscle contraction / adenylate cyclase-inhibiting adrenergic receptor signaling pathway / phospholipase C-activating adrenergic receptor signaling pathway / alpha2-adrenergic receptor activity / Adrenaline signalling through Alpha-2 adrenergic receptor / alpha-2C adrenergic receptor binding / receptor transactivation / epinephrine binding / alpha-1B adrenergic receptor binding / negative regulation of norepinephrine secretion / negative regulation of epinephrine secretion / negative regulation of calcium ion transmembrane transporter activity / heterotrimeric G-protein binding / dopaminergic synapse / negative regulation of calcium ion-dependent exocytosis / Surfactant metabolism / positive regulation of potassium ion transport / thermoception / fear response / thioesterase binding / negative regulation of insulin secretion involved in cellular response to glucose stimulus / vesicle docking involved in exocytosis / positive regulation of membrane protein ectodomain proteolysis / norepinephrine binding / Adrenoceptors / intestinal absorption / positive regulation of epidermal growth factor receptor signaling pathway / G protein-coupled dopamine receptor signaling pathway / regulation of heart contraction / positive regulation of wound healing / adrenergic receptor signaling pathway / activation of protein kinase activity / negative regulation of calcium ion transport / Rho protein signal transduction / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding / regulation of vasoconstriction / GABA-ergic synapse / negative regulation of insulin secretion / negative regulation of lipid catabolic process / G protein-coupled serotonin receptor binding / presynaptic active zone membrane / axon terminus / adenylate cyclase-activating adrenergic receptor signaling pathway / cellular response to hormone stimulus / presynaptic modulation of chemical synaptic transmission / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / activation of protein kinase B activity / positive regulation of cytokine production / locomotory behavior / muscle contraction / female pregnancy / postsynaptic density membrane / positive regulation of MAP kinase activity / 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 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G-protein activation / 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 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / platelet activation / 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 / vasodilation / 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 / 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 / glucose homeostasis / retina development in camera-type eye 類似検索 - 分子機能 | ||||||
生物種 | ![]() ![]() ![]() | ||||||
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: 3.47 Å | ||||||
![]() | Xu, J. / Fink, E.A. / Shoichet, B.K. / Du, Y. | ||||||
資金援助 | 1件
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![]() | ![]() タイトル: Structure-based discovery of nonopioid analgesics acting through the α-adrenergic receptor. 著者: Elissa A Fink / Jun Xu / Harald Hübner / Joao M Braz / Philipp Seemann / Charlotte Avet / Veronica Craik / Dorothee Weikert / Maximilian F Schmidt / Chase M Webb / Nataliya A Tolmachova / ...著者: Elissa A Fink / Jun Xu / Harald Hübner / Joao M Braz / Philipp Seemann / Charlotte Avet / Veronica Craik / Dorothee Weikert / Maximilian F Schmidt / Chase M Webb / Nataliya A Tolmachova / Yurii S Moroz / Xi-Ping Huang / Chakrapani Kalyanaraman / Stefan Gahbauer / Geng Chen / Zheng Liu / Matthew P Jacobson / John J Irwin / Michel Bouvier / Yang Du / Brian K Shoichet / Allan I Basbaum / Peter Gmeiner / ![]() ![]() ![]() ![]() ![]() ![]() 要旨: Because nonopioid analgesics are much sought after, we computationally docked more than 301 million virtual molecules against a validated pain target, the α-adrenergic receptor (αAR), seeking new ...Because nonopioid analgesics are much sought after, we computationally docked more than 301 million virtual molecules against a validated pain target, the α-adrenergic receptor (αAR), seeking new αAR agonists chemotypes that lack the sedation conferred by known αAR drugs, such as dexmedetomidine. We identified 17 ligands with potencies as low as 12 nanomolar, many with partial agonism and preferential G and G signaling. Experimental structures of αAR complexed with two of these agonists confirmed the docking predictions and templated further optimization. Several compounds, including the initial docking hit '9087 [mean effective concentration (EC) of 52 nanomolar] and two analogs, '7075 and PS75 (EC 4.1 and 4.8 nanomolar), exerted on-target analgesic activity in multiple in vivo pain models without sedation. These newly discovered agonists are interesting as therapeutic leads that lack the liabilities of opioids and the sedation of dexmedetomidine. | ||||||
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構造の表示
構造ビューア | 分子: ![]() ![]() |
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ダウンロードとリンク
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ダウンロード
PDBx/mmCIF形式 | ![]() | 202.3 KB | 表示 | ![]() |
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PDB形式 | ![]() | 157.4 KB | 表示 | ![]() |
PDBx/mmJSON形式 | ![]() | ツリー表示 | ![]() | |
その他 | ![]() |
-検証レポート
文書・要旨 | ![]() | 854.8 KB | 表示 | ![]() |
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文書・詳細版 | ![]() | 874.9 KB | 表示 | |
XML形式データ | ![]() | 37.2 KB | 表示 | |
CIF形式データ | ![]() | 55.6 KB | 表示 | |
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-関連構造データ
関連構造データ | ![]() 32331MC ![]() 7w7eC 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 ( |
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類似構造データ | 類似検索 - 機能・相同性 ![]() |
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リンク
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集合体
登録構造単位 | ![]()
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要素
-Guanine nucleotide-binding protein ... , 3種, 3分子 ABG
#1: タンパク質 | 分子量: 40100.500 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() |
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#2: タンパク質 | 分子量: 38402.867 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() |
#3: 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) ![]() ![]() |
-抗体 / タンパク質 / 非ポリマー , 3種, 3分子 HR![](data/chem/img/W96.gif)
![](data/chem/img/W96.gif)
#4: 抗体 | 分子量: 32898.781 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() ![]() |
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#5: タンパク質 | 分子量: 50704.566 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 発現宿主: ![]() ![]() 参照: UniProt: P08913 |
#6: 化合物 | ChemComp-W96 / |
-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 |
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試料調製
構成要素 | 名称: Signaling complex of alpha2A adrenergic receptor with GoA タイプ: COMPLEX / Entity ID: #1-#5 / 由来: RECOMBINANT | ||||||||||||
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分子量 | 実験値: NO | ||||||||||||
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 |
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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: ![]() |
電子レンズ | モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 2000 nm / 最小 デフォーカス(公称値): 1000 nm |
撮影 | 電子線照射量: 60 e/Å2 フィルム・検出器のモデル: GATAN K3 BIOQUANTUM (6k x 4k) |
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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: 3.47 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 287431 / 対称性のタイプ: POINT |