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基本情報
登録情報 | データベース: PDB / ID: 8xvk | |||||||||||||||||||||||||||||||||||||||
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タイトル | Cryo-EM structure of ETAR bound with Ambrisentan | |||||||||||||||||||||||||||||||||||||||
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![]() | SIGNALING PROTEIN / GPCR / COMPLEX / ETA / AMBRISENTAN | |||||||||||||||||||||||||||||||||||||||
機能・相同性 | ![]() regulation of protein localization to cell leading edge / endothelin receptor activity / cellular response to human chorionic gonadotropin stimulus / meiotic cell cycle process involved in oocyte maturation / semaphorin-plexin signaling pathway involved in axon guidance / neural crest cell fate commitment / glomerular endothelium development / sympathetic neuron axon guidance / noradrenergic neuron differentiation / atrial cardiac muscle tissue development ...regulation of protein localization to cell leading edge / endothelin receptor activity / cellular response to human chorionic gonadotropin stimulus / meiotic cell cycle process involved in oocyte maturation / semaphorin-plexin signaling pathway involved in axon guidance / neural crest cell fate commitment / glomerular endothelium development / sympathetic neuron axon guidance / noradrenergic neuron differentiation / atrial cardiac muscle tissue development / vascular associated smooth muscle cell development / cardiac chamber formation / heparin proteoglycan metabolic process / pharyngeal arch artery morphogenesis / regulation of D-glucose transmembrane transport / endothelin receptor signaling pathway involved in heart process / cardiac neural crest cell migration involved in outflow tract morphogenesis / endothelin receptor signaling pathway / response to acetylcholine / podocyte differentiation / podocyte apoptotic process / developmental pigmentation / positive regulation of cation channel activity / left ventricular cardiac muscle tissue morphogenesis / embryonic skeletal system development / sodium ion homeostasis / renal sodium ion absorption / enteric nervous system development / mesenchymal cell apoptotic process / axonogenesis involved in innervation / glomerular filtration / protein transmembrane transport / artery smooth muscle contraction / renal albumin absorption / cellular response to follicle-stimulating hormone stimulus / cellular response to luteinizing hormone stimulus / vasoconstriction / respiratory gaseous exchange by respiratory system / sympathetic nervous system development / cranial skeletal system development / phosphatidylinositol-4,5-bisphosphate phospholipase C activity / norepinephrine metabolic process / cellular response to toxic substance / embryonic heart tube development / axon extension / establishment of endothelial barrier / cellulase / aorta development / middle ear morphogenesis / cellulase activity / neuromuscular process / neuron remodeling / beta-glucosidase activity / branching involved in blood vessel morphogenesis / face development / thyroid gland development / cAMP/PKA signal transduction / blood vessel remodeling / smooth muscle contraction / canonical Wnt signaling pathway / cellulose catabolic process / activation of adenylate cyclase activity / response to amphetamine / regulation of heart rate / Peptide ligand-binding receptors / mitochondrion organization / electron transport chain / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / calcium ion transmembrane transport / regulation of blood pressure / response to wounding / intracellular calcium ion homeostasis / mitotic cell cycle / positive regulation of cytosolic calcium ion concentration / cellular response to oxidative stress / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / in utero embryonic development / gene expression / response to hypoxia / periplasmic space / electron transfer activity / positive regulation of canonical NF-kappaB signal transduction / cell population proliferation / G protein-coupled receptor signaling pathway / iron ion binding / heme binding / cell surface / signal transduction / extracellular region / plasma membrane 類似検索 - 分子機能 | |||||||||||||||||||||||||||||||||||||||
生物種 | ![]() synthetic construct (人工物) ![]() ![]() ![]() | |||||||||||||||||||||||||||||||||||||||
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: 3.21 Å | |||||||||||||||||||||||||||||||||||||||
![]() | Hou, J.Y. / Liu, S.H. / Wu, L.J. / Liu, Z.J. / Hua, T. | |||||||||||||||||||||||||||||||||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Structural basis of antagonist selectivity in endothelin receptors. 著者: Junyi Hou / Shenhui Liu / Xiaodan Zhang / Guowei Tu / Lijie Wu / Yijie Zhang / Hao Yang / Xiangcheng Li / Junlin Liu / Longquan Jiang / Qiwen Tan / Fang Bai / Zhijie Liu / Changhong Miao / Tian Hua / Zhe Luo / ![]() 要旨: Endothelins and their receptors, ET and ET, play vital roles in maintaining vascular homeostasis. Therapeutically targeting endothelin receptors, particularly through ET antagonists, has shown ...Endothelins and their receptors, ET and ET, play vital roles in maintaining vascular homeostasis. Therapeutically targeting endothelin receptors, particularly through ET antagonists, has shown efficacy in treating pulmonary arterial hypertension (PAH) and other cardiovascular- and renal-related diseases. Here we present cryo-electron microscopy structures of ET in complex with two PAH drugs, macitentan and ambrisentan, along with zibotentan, a selective ET antagonist, respectively. Notably, a specialized anti-ET antibody facilitated the structural elucidation. These structures, together with the active-state structures of ET-1-bound ET and ET, and the agonist BQ3020-bound ET, in complex with G, unveil the molecular basis of agonist/antagonist binding modes in endothelin receptors. Key residues that confer antagonist selectivity to endothelin receptors were identified along with the activation mechanism of ET. Furthermore, our results suggest that ECL2 in ET can serve as an epitope for antibody-mediated receptor antagonism. Collectively, these insights establish a robust theoretical framework for the rational design of small-molecule drugs and antibodies with selective activity against endothelin receptors. | |||||||||||||||||||||||||||||||||||||||
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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 | ![]() | 210.5 KB | 表示 | ![]() |
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PDB形式 | ![]() | 表示 | ![]() | |
PDBx/mmJSON形式 | ![]() | ツリー表示 | ![]() | |
その他 | ![]() |
-検証レポート
文書・要旨 | ![]() | 472.2 KB | 表示 | ![]() |
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文書・詳細版 | ![]() | 485.6 KB | 表示 | |
XML形式データ | ![]() | 20.5 KB | 表示 | |
CIF形式データ | ![]() | 31.6 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 | ![]() 38707MC ![]() 8xveC ![]() 8xvhC ![]() 8xviC ![]() 8xvjC ![]() 8xvlC 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
#1: 抗体 | 分子量: 28577.918 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 発現宿主: Mammalian expression vector Flag-MCS-pcDNA3.1 (その他) |
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#2: 抗体 | 分子量: 15071.431 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) synthetic construct (人工物) / 発現宿主: ![]() ![]() |
#3: 抗体 | 分子量: 25575.604 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 発現宿主: Mammalian expression vector Flag-MCS-pcDNA3.1 (その他) |
#4: タンパク質 | 分子量: 89090.867 Da / 分子数: 1 / 由来タイプ: 組換発現 由来: (組換発現) ![]() ![]() ![]() ![]() 遺伝子: celH, Cthe_1472, EDNRA, ETA, ETRA, cybC 発現宿主: ![]() ![]() 参照: UniProt: P16218, UniProt: P25101, UniProt: P0ABE7, cellulase |
#5: 化合物 | ChemComp-A1D5J / 分子量: 378.421 Da / 分子数: 1 / 由来タイプ: 合成 / 式: C22H22N2O4 |
研究の焦点であるリガンドがあるか | Y |
Has protein modification | 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 |
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試料調製
構成要素 | 名称: Complex of Endothelin receptor type A with ambrisentan タイプ: COMPLEX / Entity ID: #1-#4 / 由来: RECOMBINANT |
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由来(天然) | 生物種: ![]() |
由来(組換発現) | 生物種: ![]() ![]() |
緩衝液 | pH: 7.4 |
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: FEI FALCON IV (4k x 4k) |
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解析
EMソフトウェア | 名称: PHENIX / カテゴリ: モデル精密化 | ||||||||||||||||||||||||
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CTF補正 | タイプ: NONE | ||||||||||||||||||||||||
3次元再構成 | 解像度: 3.21 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 568027 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
拘束条件 |
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