登録情報 データベース : EMDB / ID : EMD-38707 ダウンロードとリンクタイトル Cryo-EM structure of ETAR bound with Ambrisentan マップデータ 詳細 試料複合体 : Complex of Endothelin receptor type A with ambrisentanタンパク質・ペプチド : anti-BRIL Fab Heavy chainタンパク質・ペプチド : anti-Fab Nanobodyタンパク質・ペプチド : anti-BRIL Fab Light chainタンパク質・ペプチド : Endoglucanase H,Endothelin-1 receptor,Soluble cytochrome b562リガンド : Ambrisentan 詳細 キーワード GPCR / COMPLEX / ETA / AMBRISENTAN / SIGNALING PROTEIN機能・相同性 機能・相同性情報分子機能 ドメイン・相同性 構成要素
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 / establishment of endothelial barrier / axon extension / cellulase / aorta development / middle ear morphogenesis / cellulase activity / neuromuscular process / beta-glucosidase activity / neuron remodeling / branching involved in blood vessel morphogenesis / face development / thyroid gland development / cAMP/PKA signal transduction / smooth muscle contraction / blood vessel remodeling / canonical Wnt signaling pathway / cellulose catabolic process / activation of adenylate cyclase activity / regulation of heart rate / Peptide ligand-binding receptors / response to amphetamine / 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 / gene expression / in utero embryonic development / periplasmic space / response to hypoxia / electron transfer activity / cell population proliferation / positive regulation of canonical NF-kappaB signal transduction / 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 Endothelin receptor A / Endothelin receptor family / : / Carbohydrate binding module family 11 / Carbohydrate binding domain (family 11) / Glycosyl hydrolase family 26 / Glycosyl hydrolase family 26 domain / Glycosyl hydrolases family 26 (GH26) domain profile. / : / Clostridium cellulosome enzymes repeated domain signature. ... Endothelin receptor A / Endothelin receptor family / : / Carbohydrate binding module family 11 / Carbohydrate binding domain (family 11) / Glycosyl hydrolase family 26 / Glycosyl hydrolase family 26 domain / Glycosyl hydrolases family 26 (GH26) domain profile. / : / Clostridium cellulosome enzymes repeated domain signature. / Glycoside hydrolase, family 5, conserved site / Glycosyl hydrolases family 5 signature. / Dockerin domain / Dockerin domain profile. / Dockerin type I domain / Dockerin type I repeat / Dockerin domain superfamily / Glycoside hydrolase, family 5 / Cellulase (glycosyl hydrolase family 5) / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Galactose-binding-like domain superfamily / EF-hand calcium-binding domain. / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / Glycoside hydrolase superfamily 類似検索 - ドメイン・相同性 Soluble cytochrome b562 / Endoglucanase H / Endothelin-1 receptor 類似検索 - 構成要素生物種 Homo sapiens (ヒト) / synthetic construct (人工物) 手法 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度 : 3.21 Å 詳細 データ登録者Hou JY / Liu SH / Wu LJ / Liu ZJ / Hua T 資金援助 中国, 1件 詳細 詳細を隠すOrganization Grant number 国 Not funded 中国
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 登録 2024年1月15日 - ヘッダ(付随情報) 公開 2024年8月28日 - マップ公開 2024年8月28日 - 更新 2025年7月23日 - 現状 2025年7月23日 処理サイト : PDBc / 状態 : 公開
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