+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 8xvi | ||||||
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タイトル | Cryo-EM structure of ETAR bound with Endothelin1 | ||||||
要素 |
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キーワード | SIGNALING PROTEIN / GPCR / COMPLEX / ETA / ENDOTHELIN-1 | ||||||
機能・相同性 | 機能・相同性情報 regulation of protein localization to cell leading edge / positive regulation of prostaglandin-endoperoxide synthase activity / endothelin A receptor binding / protein kinase C deactivation / phospholipase D-activating G protein-coupled receptor signaling pathway / rhythmic excitation / endothelin B receptor binding / endothelin receptor activity / peptide hormone secretion / cellular response to human chorionic gonadotropin stimulus ...regulation of protein localization to cell leading edge / positive regulation of prostaglandin-endoperoxide synthase activity / endothelin A receptor binding / protein kinase C deactivation / phospholipase D-activating G protein-coupled receptor signaling pathway / rhythmic excitation / endothelin B receptor binding / endothelin receptor activity / peptide hormone secretion / cellular response to human chorionic gonadotropin stimulus / meiotic cell cycle process involved in oocyte maturation / positive regulation of artery morphogenesis / body fluid secretion / neural crest cell fate commitment / vein smooth muscle contraction / sympathetic neuron axon guidance / atrial cardiac muscle tissue development / response to prostaglandin F / glomerular endothelium development / positive regulation of sarcomere organization / vascular associated smooth muscle cell development / noradrenergic neuron differentiation / semaphorin-plexin signaling pathway involved in axon guidance / histamine secretion / positive regulation of renal sodium excretion / leukocyte activation / positive regulation of chemokine-mediated signaling pathway / cardiac chamber formation / maternal process involved in parturition / heparin metabolic process / rough endoplasmic reticulum lumen / pharyngeal arch artery morphogenesis / regulation of D-glucose transmembrane transport / positive regulation of odontogenesis / epithelial fluid transport / response to leptin / endothelin receptor signaling pathway involved in heart process / negative regulation of hormone secretion / cardiac neural crest cell migration involved in outflow tract morphogenesis / Weibel-Palade body / sodium ion homeostasis / endothelin receptor signaling pathway / response to acetylcholine / response to ozone / developmental pigmentation / podocyte differentiation / positive regulation of cell growth involved in cardiac muscle cell development / podocyte apoptotic process / renal sodium ion absorption / mesenchymal cell apoptotic process / embryonic skeletal system development / left ventricular cardiac muscle tissue morphogenesis / artery smooth muscle contraction / glomerular filtration / protein transmembrane transport / enteric nervous system development / axonogenesis involved in innervation / positive regulation of cation channel activity / cranial skeletal system development / cellular response to follicle-stimulating hormone stimulus / positive regulation of prostaglandin secretion / cellular response to luteinizing hormone stimulus / negative regulation of nitric-oxide synthase biosynthetic process / cellular response to mineralocorticoid stimulus / renal albumin absorption / basal part of cell / positive regulation of smooth muscle contraction / respiratory gaseous exchange by respiratory system / regulation of pH / sympathetic nervous system development / response to salt / positive regulation of urine volume / phosphatidylinositol phospholipase C activity / positive regulation of hormone secretion / norepinephrine metabolic process / regulation of systemic arterial blood pressure by endothelin / vasoconstriction / : / negative regulation of blood coagulation / embryonic heart tube development / dorsal/ventral pattern formation / axon extension / superoxide anion generation / establishment of endothelial barrier / positive regulation of neutrophil chemotaxis / aorta development / positive regulation of signaling receptor activity / cartilage development / middle ear morphogenesis / : / cellular response to glucocorticoid stimulus / negative regulation of protein metabolic process / cellulase / prostaglandin biosynthetic process / cellular response to fatty acid / neuromuscular process / nitric oxide transport / beta-glucosidase activity / positive regulation of heart rate / cellulase activity 類似検索 - 分子機能 | ||||||
生物種 | Homo sapiens (ヒト) Lama glama (ラマ) Acetivibrio thermocellus ATCC 27405 (バクテリア) | ||||||
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: 3.32 Å | ||||||
データ登録者 | Hou, J.Y. / Liu, S.H. / Wu, L.J. / Liu, Z.J. / Hua, T. | ||||||
資金援助 | 中国, 1件
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引用 | ジャーナル: Cell Discov / 年: 2024 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. | ||||||
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 | 8xvi.cif.gz | 235.6 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb8xvi.ent.gz | 179 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 8xvi.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 | 8xvi_validation.pdf.gz | 1.4 MB | 表示 | wwPDB検証レポート |
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文書・詳細版 | 8xvi_full_validation.pdf.gz | 1.4 MB | 表示 | |
XML形式データ | 8xvi_validation.xml.gz | 44.4 KB | 表示 | |
CIF形式データ | 8xvi_validation.cif.gz | 66 KB | 表示 | |
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/xv/8xvi ftp://data.pdbj.org/pub/pdb/validation_reports/xv/8xvi | HTTPS FTP |
-関連構造データ
関連構造データ | 38705MC 8xveC 8xvhC 8xvjC 8xvkC 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 (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
-タンパク質 , 2種, 2分子 AR
#1: タンパク質 | 分子量: 30464.314 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: Escherichia coli (大腸菌) |
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#5: タンパク質 | 分子量: 77879.422 Da / 分子数: 1 / 由来タイプ: 組換発現 由来: (組換発現) Acetivibrio thermocellus ATCC 27405 (バクテリア), (組換発現) Homo sapiens (ヒト) 遺伝子: celH, Cthe_1472, EDNRA, ETA, ETRA 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 参照: UniProt: P16218, UniProt: P25101, cellulase |
-Guanine nucleotide-binding protein ... , 2種, 2分子 BG
#2: タンパク質 | 分子量: 38045.629 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 |
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#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) 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 |
-抗体 / タンパク質・ペプチド , 2種, 2分子 NT
#4: 抗体 | 分子量: 17057.271 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: Escherichia coli (大腸菌) |
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#6: タンパク質・ペプチド | 分子量: 2497.951 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: EDN1 / 発現宿主: Homo sapiens (ヒト) / 参照: UniProt: P05305 |
-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: Complex of protein Gs/q with ETA and Endothelin-1 / タイプ: COMPLEX / Entity ID: all / 由来: RECOMBINANT |
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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) |
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 |
-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): 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) |
-解析
CTF補正 | タイプ: NONE | ||||||||||||||||||||||||
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3次元再構成 | 解像度: 3.32 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 114666 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
拘束条件 |
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