+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 5aav | ||||||
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タイトル | Optimization of a novel binding motif to to (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H- pyrido(3,4-b)indol-1-yl)phenyl)acrylic acid (AZD9496), a potent and orally bioavailable selective estrogen receptor downregulator and antagonist | ||||||
要素 | (ESTROGEN RECEPTORエストロゲン受容体) x 2 | ||||||
キーワード | SIGNALING PROTEIN / BREAST CANCER / ESTROGEN RECEPTOR DOWNREGULATOR / FULVESTRANT (フルベストラント) / AZD9496 / NUCLEAR HORMONE RECEPTOR (核内受容体) | ||||||
機能・相同性 | 機能・相同性情報 regulation of epithelial cell apoptotic process / antral ovarian follicle growth / G protein-coupled estrogen receptor activity / regulation of branching involved in prostate gland morphogenesis / RUNX1 regulates transcription of genes involved in WNT signaling / RUNX1 regulates estrogen receptor mediated transcription / regulation of toll-like receptor signaling pathway / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / nuclear estrogen receptor activity / epithelial cell proliferation involved in mammary gland duct elongation ...regulation of epithelial cell apoptotic process / antral ovarian follicle growth / G protein-coupled estrogen receptor activity / regulation of branching involved in prostate gland morphogenesis / RUNX1 regulates transcription of genes involved in WNT signaling / RUNX1 regulates estrogen receptor mediated transcription / regulation of toll-like receptor signaling pathway / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / nuclear estrogen receptor activity / epithelial cell proliferation involved in mammary gland duct elongation / epithelial cell development / prostate epithelial cord elongation / negative regulation of smooth muscle cell apoptotic process / mammary gland branching involved in pregnancy / uterus development / vagina development / TFIIB-class transcription factor binding / androgen metabolic process / steroid hormone mediated signaling pathway / mammary gland alveolus development / intracellular estrogen receptor signaling pathway / cellular response to estrogen stimulus / estrogen response element binding / : / intracellular steroid hormone receptor signaling pathway / negative regulation of canonical NF-kappaB signal transduction / Nuclear signaling by ERBB4 / RNA polymerase II preinitiation complex assembly / protein localization to chromatin / 14-3-3 protein binding / TBP-class protein binding / steroid binding / nitric-oxide synthase regulator activity / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / ESR-mediated signaling / transcription corepressor binding / negative regulation of miRNA transcription / cellular response to estradiol stimulus / transcription coregulator binding / 細胞分化 / nuclear estrogen receptor binding / positive regulation of nitric-oxide synthase activity / SUMOylation of intracellular receptors / ユークロマチン / negative regulation of DNA-binding transcription factor activity / beta-catenin binding / transcription coactivator binding / positive regulation of DNA-binding transcription factor activity / Nuclear Receptor transcription pathway / response to estrogen / Regulation of RUNX2 expression and activity / Constitutive Signaling by Aberrant PI3K in Cancer / nuclear receptor activity / positive regulation of nitric oxide biosynthetic process / male gonad development / positive regulation of fibroblast proliferation / sequence-specific double-stranded DNA binding / Ovarian tumor domain proteases / PIP3 activates AKT signaling / response to estradiol / phospholipase C-activating G protein-coupled receptor signaling pathway / ATPase binding / positive regulation of cytosolic calcium ion concentration / regulation of inflammatory response / fibroblast proliferation / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / DNA-binding transcription activator activity, RNA polymerase II-specific / Estrogen-dependent gene expression / transcription regulator complex / Extra-nuclear estrogen signaling / calmodulin binding / DNA-binding transcription factor activity, RNA polymerase II-specific / クロマチンリモデリング / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / negative regulation of gene expression / chromatin binding / クロマチン / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / protein kinase binding / positive regulation of DNA-templated transcription / ゴルジ体 / enzyme binding / negative regulation of transcription by RNA polymerase II / シグナル伝達 / positive regulation of transcription by RNA polymerase II / protein-containing complex / zinc ion binding / 核質 / 生体膜 / identical protein binding / 細胞核 / 細胞膜 / 細胞質基質 / 細胞質 類似検索 - 分子機能 | ||||||
生物種 | HOMO SAPIENS (ヒト) | ||||||
手法 | X線回折 / シンクロトロン / 分子置換 / 解像度: 1.95 Å | ||||||
データ登録者 | Norman, R.A. / Bradbury, R.H. / de Almeida, C. / Andrews, D.M. / Ballard, P. / Buttar, D. / Callis, R.J. / Currie, G.S. / Curwen, J.O. / Davies, C.D. ...Norman, R.A. / Bradbury, R.H. / de Almeida, C. / Andrews, D.M. / Ballard, P. / Buttar, D. / Callis, R.J. / Currie, G.S. / Curwen, J.O. / Davies, C.D. / de Savi, C. / Donald, C.S. / Feron, L.J.L. / Glossop, S.C. / Hayter, B.R. / Karoutchi, G. / Lamont, S.G. / MacFaul, P. / Moss, T. / Pearson, S.E. / Rabow, A.A. / Tonge, M. / Walker, G.E. / Weir, H.M. / Wilson, Z. | ||||||
引用 | ジャーナル: J.Med.Chem. / 年: 2015 タイトル: Optimization of a Novel Binding Motif to (E)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-Fluoro-2-Methylpropyl)-3-Methyl-2, 3,4,9-Tetrahydro-1H-Pyrido[3,4-B]Indol-1-Yl)Phenyl)Acrylic Acid (Azd9496) ...タイトル: Optimization of a Novel Binding Motif to (E)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-Fluoro-2-Methylpropyl)-3-Methyl-2, 3,4,9-Tetrahydro-1H-Pyrido[3,4-B]Indol-1-Yl)Phenyl)Acrylic Acid (Azd9496), a Potent and Orally Bioavailable Selective Estrogen Receptor Downregulator and Antagonist. 著者: De Savi, C. / Bradbury, R.H. / Rabow, A.A. / Norman, R.A. / De Almeida, C. / Andrews, D.M. / Ballard, P. / Buttar, D. / Callis, R. / Currie, G.S. / Davies, C. / Donald, C. / Feron, L. / ...著者: De Savi, C. / Bradbury, R.H. / Rabow, A.A. / Norman, R.A. / De Almeida, C. / Andrews, D.M. / Ballard, P. / Buttar, D. / Callis, R. / Currie, G.S. / Davies, C. / Donald, C. / Feron, L. / Hayter, B.R. / Hussain, S. / Karoutchi, G. / Lamont, S. / Macfaul, P.A. / Moss, T.A. / Pearson, S. / Tonge, M. / Walker, G. / Weir, H. / Wilson, Z. #1: ジャーナル: Cancer Res. / 年: 2016 タイトル: Azd9496: An Oral Estrogen Receptor Inhibitor that Blocks the Growth of Er-Positive and Esr1-Mutant Breast Tumors in Preclinical Models. 著者: Weir, H.M. / Bradbury, R.H. / Lawson, M. / Rabow, A.A. / Buttar, D. / Callis, R.J. / Curwen, J.O. / De Almeida, C. / Ballard, P. / Hulse, M. / Donald, C.S. / Feron, L.J.L. / Karoutchi, G. / ...著者: Weir, H.M. / Bradbury, R.H. / Lawson, M. / Rabow, A.A. / Buttar, D. / Callis, R.J. / Curwen, J.O. / De Almeida, C. / Ballard, P. / Hulse, M. / Donald, C.S. / Feron, L.J.L. / Karoutchi, G. / Macfaul, P. / Moss, T. / Norman, R.A. / Pearson, S.E. / Tonge, M. / Davies, G. / Walker, G.E. / Wilson, Z. / Rowlinson, R. / Powell, S. / Sadler, C. / Richmond, G. / Ladd, B. / Pazolli, E. / Mazzola, A.M. / D'Cruz, C. / De Savi, C. | ||||||
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 | 5aav.cif.gz | 147.2 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb5aav.ent.gz | 115.9 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 5aav.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
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/aa/5aav ftp://data.pdbj.org/pub/pdb/validation_reports/aa/5aav | HTTPS FTP |
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-関連構造データ
-リンク
-集合体
登録構造単位 |
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単位格子 |
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-要素
#1: タンパク質 | 分子量: 28655.521 Da / 分子数: 1 / 断片: LIGAND-BINDING DOMAIN / 変異: YES / 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) / 株 (発現宿主): BL21(DE3) / Variant (発現宿主): GOLD / 参照: UniProt: P03372 | ||
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#2: タンパク質 | 分子量: 28637.482 Da / 分子数: 1 / 断片: LIGAND-BINDING DOMAIN / 変異: YES / 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) / 株 (発現宿主): BL21(DE3) / Variant (発現宿主): GOLD / 参照: UniProt: P03372 | ||
#3: 化合物 | #4: 水 | ChemComp-HOH / | |
-実験情報
-実験
実験 | 手法: X線回折 / 使用した結晶の数: 1 |
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-試料調製
結晶 | マシュー密度: 2.02 Å3/Da / 溶媒含有率: 39.22 % / 解説: NONE |
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結晶化 | pH: 6.5 詳細: 0.1 M PCTP, PH 6.5 (0.04 M SODIUM PROPIONATE, 0.02 M SODIUM CACODYLATE, 0.04 M BIS-TRIS PROPANE), 22% PEG3350, 0.2M MGCL2 |
-データ収集
回折 | 平均測定温度: 100 K |
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放射光源 | 由来: シンクロトロン / サイト: Diamond / ビームライン: I04 / 波長: 0.96 |
検出器 | タイプ: DECTRIS PILATUS 6M / 検出器: PIXEL |
放射 | プロトコル: SINGLE WAVELENGTH / 単色(M)・ラウエ(L): M / 散乱光タイプ: x-ray |
放射波長 | 波長: 0.96 Å / 相対比: 1 |
反射 | 解像度: 1.95→52.7 Å / Num. obs: 30991 / % possible obs: 99 % / Observed criterion σ(I): 2 / 冗長度: 6.4 % / Rmerge(I) obs: 0.1 / Net I/σ(I): 16.3 |
反射 シェル | 解像度: 1.95→2.06 Å / 冗長度: 6.5 % / Rmerge(I) obs: 0.37 / Mean I/σ(I) obs: 4.7 / % possible all: 99.9 |
-解析
ソフトウェア |
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精密化 | 構造決定の手法: 分子置換 開始モデル: IN HOUSE MODEL 解像度: 1.95→44.32 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.919 / SU B: 8.947 / SU ML: 0.115 / 交差検証法: THROUGHOUT / ESU R: 0.185 / ESU R Free: 0.16 / 立体化学のターゲット値: MAXIMUM LIKELIHOOD 詳細: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES WITH TLS ADDED
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溶媒の処理 | イオンプローブ半径: 0.8 Å / 減衰半径: 0.8 Å / VDWプローブ半径: 1.2 Å / 溶媒モデル: MASK | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
原子変位パラメータ | Biso mean: 28.491 Å2
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精密化ステップ | サイクル: LAST / 解像度: 1.95→44.32 Å
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拘束条件 |
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