+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 2h96 | ||||||
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タイトル | Discovery of Potent, Highly Selective, and Orally Bioavailable Pyridine Carboxamide C-jun NH2-terminal Kinase Inhibitors | ||||||
要素 |
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キーワード | TRANSCRIPTION (転写 (生物学)) / JNK1 / C-JUN N-TERMINAL KINASE (C-Jun N末端キナーゼ) / PROTEIN KINASE JNK1 INHIBITORS / PYRIDINE CARBOXAMIDE INHIBITORS | ||||||
機能・相同性 | 機能・相同性情報 positive regulation of cell killing / dentate gyrus mossy fiber / JUN phosphorylation / regulation of CD8-positive, alpha-beta T cell proliferation / regulation of DNA replication origin binding / Interleukin-38 signaling / Activation of BMF and translocation to mitochondria / basal dendrite / Activation of BIM and translocation to mitochondria / JUN kinase activity ...positive regulation of cell killing / dentate gyrus mossy fiber / JUN phosphorylation / regulation of CD8-positive, alpha-beta T cell proliferation / regulation of DNA replication origin binding / Interleukin-38 signaling / Activation of BMF and translocation to mitochondria / basal dendrite / Activation of BIM and translocation to mitochondria / JUN kinase activity / WNT5:FZD7-mediated leishmania damping / negative regulation of JUN kinase activity / MAP-kinase scaffold activity / JUN kinase binding / positive regulation of cyclase activity / histone deacetylase regulator activity / positive regulation of NLRP3 inflammasome complex assembly / DSCAM interactions / protein serine/threonine kinase binding / NRAGE signals death through JNK / protein kinase inhibitor activity / Activation of the AP-1 family of transcription factors / Fc-epsilon receptor signaling pathway / kinesin binding / regulation of JNK cascade / regulation of macroautophagy / 分裂促進因子活性化タンパク質キナーゼ / stress-activated MAPK cascade / negative regulation of intrinsic apoptotic signaling pathway / response to mechanical stimulus / response to UV / vesicle-mediated transport / JNK cascade / cellular response to cadmium ion / positive regulation of protein metabolic process / cellular response to amino acid starvation / NRIF signals cell death from the nucleus / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / negative regulation of protein binding / ミトコンドリア / FCERI mediated MAPK activation / positive regulation of JNK cascade / peptidyl-threonine phosphorylation / regulation of circadian rhythm / cellular response to reactive oxygen species / histone deacetylase binding / cellular response to mechanical stimulus / regulation of protein localization / 細胞老化 / rhythmic process / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / cellular response to oxidative stress / peptidyl-serine phosphorylation / protein phosphatase binding / Oxidative Stress Induced Senescence / response to oxidative stress / cellular response to lipopolysaccharide / positive regulation of apoptotic process / 神経繊維 / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / neuronal cell body / シナプス / 樹状突起 / endoplasmic reticulum membrane / regulation of DNA-templated transcription / positive regulation of gene expression / negative regulation of apoptotic process / perinuclear region of cytoplasm / enzyme binding / 核質 / ATP 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: 3 Å | ||||||
データ登録者 | Abad-Zapatero, C. | ||||||
引用 | ジャーナル: J.Med.Chem. / 年: 2006 タイトル: Discovery of potent, highly selective, and orally bioavailable pyridine carboxamide c-Jun NH2-terminal kinase inhibitors. 著者: Zhao, H. / Serby, M.D. / Xin, Z. / Szczepankiewicz, B.G. / Liu, M. / Kosogof, C. / Liu, B. / Nelson, L.T. / Johnson, E.F. / Wang, S. / Pederson, T. / Gum, R.J. / Clampit, J.E. / Haasch, D.L. ...著者: Zhao, H. / Serby, M.D. / Xin, Z. / Szczepankiewicz, B.G. / Liu, M. / Kosogof, C. / Liu, B. / Nelson, L.T. / Johnson, E.F. / Wang, S. / Pederson, T. / Gum, R.J. / Clampit, J.E. / Haasch, D.L. / Abad-Zapatero, C. / Fry, E.H. / Rondinone, C. / Trevillyan, J.M. / Sham, H.L. / Liu, G. #1: ジャーナル: J.Med.Chem. / 年: 2006 タイトル: Aminopyridine-Based c-Jun N-Terminal Kinase Inhibitors with Cellular Activity and Minimal Cross-Kinase Activity. 著者: Szczepankiewicz, B.G. / Kosogof, C. / Nelson, L.T. / Liu, G. / Liu, B. / Zhao, H. / Serby, M.D. / Xin, Z. / Liu, M. / Gum, R.J. / Haasch, D.L. / Wang, S. / Clampit, J.E. / Johnson, E.F. / ...著者: Szczepankiewicz, B.G. / Kosogof, C. / Nelson, L.T. / Liu, G. / Liu, B. / Zhao, H. / Serby, M.D. / Xin, Z. / Liu, M. / Gum, R.J. / Haasch, D.L. / Wang, S. / Clampit, J.E. / Johnson, E.F. / Lubben, T.H. / Stashko, M.A. / Olejniczak, E.T. / Sun, C. / Dorwin, S.A. / Haskins, K. / Abad-Zapatero, C. / Fry, E.H. / Hutchins, C.W. / Sham, H.L. / Rondinone, C.M. / Trevillyan, J.M. #2: ジャーナル: Bioorg.Med.Chem.Lett. / 年: 2006 タイトル: Synthesis and SAR of 1,9-dihydro-9-hydroxypyrazolo[3,4-b]quinolin-4-ones as novel, selective c-Jun N-terminal kinase inhibitors. 著者: Liu, M. / Xin, Z. / Clampit, J.E. / Wang, S. / Gum, R.J. / Haasch, D.L. / Trevillyan, J.M. / Abad-Zapatero, C. / Fry, E.H. / Sham, H.L. / Liu, G. | ||||||
履歴 |
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Remark 999 | SEQUENCE THE NATIVE, UNMUTATED SEQUENCE IS THE SAME AS THE P45983-2 ISOFORM. THE INTRODUCED ...SEQUENCE THE NATIVE, UNMUTATED SEQUENCE IS THE SAME AS THE P45983-2 ISOFORM. THE INTRODUCED MUTATIONS (THR183>GLU, TYR185>GLU) ARE INTENDED TO MIMIC THE ACTIVATED FORM OF THE KINASE UPON PHOSPHORYLATION OF THOSE TWO RESIDUES. |
-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 | 2h96.cif.gz | 162.6 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb2h96.ent.gz | 129.6 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 2h96.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/h9/2h96 ftp://data.pdbj.org/pub/pdb/validation_reports/h9/2h96 | HTTPS FTP |
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-関連構造データ
関連構造データ | 2g01S S: 精密化の開始モデル |
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類似構造データ |
-リンク
-集合体
登録構造単位 |
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1 |
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2 |
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3 |
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単位格子 |
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-要素
#1: タンパク質 | 分子量: 42919.559 Da / 分子数: 2 / 断片: JNK1-(1-364)-6His / 変異: T183E,Y183E / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: MAPK8, JNK1, PRKM8 / 発現宿主: Escherichia coli (大腸菌) 参照: UniProt: P45983, 分裂促進因子活性化タンパク質キナーゼ #2: タンパク質・ペプチド | 分子量: 1345.612 Da / 分子数: 2 / 断片: PEPJIP1 PEPTIDE / 由来タイプ: 合成 詳細: THE SEQUENCE IS FOUND NATURALLY IN HOMO SAPIENS (HUMAN). 参照: UniProt: Q9UQF2 #3: 化合物 | ChemComp-SO4 / #4: 化合物 | #5: 化合物 | |
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-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: 4.94 Å3/Da / 溶媒含有率: 75.11 % |
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結晶化 | pH: 6.2 詳細: PROTEIN WAS PREINCUBATED WITH THE JIP1 PEPTIDE AT A 5X MOLAR EXCESS. PROTEIN CONCENTRATION 9- 12.6 MG/ML. HANGING DROPS CONSISTED OF 2UL PROTEIN PLUS 2 UL WELL SOLUTION. WELL SOLUTION:2.8-3.1 ...詳細: PROTEIN WAS PREINCUBATED WITH THE JIP1 PEPTIDE AT A 5X MOLAR EXCESS. PROTEIN CONCENTRATION 9- 12.6 MG/ML. HANGING DROPS CONSISTED OF 2UL PROTEIN PLUS 2 UL WELL SOLUTION. WELL SOLUTION:2.8-3.1 M AMMONIUM SULFATE, 10- 14% GLYCEROL. FOR CO-CRYSTALLIZATION EXPERIMENT WITH THE COMPOUND, THE COMPOUND WAS DISSOLVED IN DMSO AT 100 MM CONCENTRATION. ALLOW TO INCUBATE FOR AT LEAST AN HOUR ON ICE. SOLUTION WAS SPUN FOR 5 MINUTES AT 2000G PRIOR TO SETTING UP FOR CRYSTALLIZATION, PH 6.2, VAPOR DIFFUSION, HANGING DROP, TEMPERATURE 277.0K, pH 6.20 |
-データ収集
回折 | 平均測定温度: 110 K |
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放射光源 | 由来: シンクロトロン / サイト: APS / ビームライン: 17-ID / 波長: 1 |
検出器 | タイプ: ADSC QUANTUM 210 / 検出器: CCD / 日付: 2004年10月18日 |
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: 1 Å / 相対比: 1 |
反射 | 解像度: 3→20 Å / Num. all: 34786 / Num. obs: 31447 / % possible obs: 89.1 % / Observed criterion σ(I): 1 / 冗長度: 7.2 % / Biso Wilson estimate: 54.6 Å2 / Rmerge(I) obs: 0.094 / Rsym value: 0.094 / Net I/σ(I): 22.5 |
反射 シェル | 解像度: 3→3.11 Å / 冗長度: 6.8 % / Rmerge(I) obs: 0.754 / Mean I/σ(I) obs: 2.2 / Num. unique all: 3461 / Rsym value: 0.754 / % possible all: 99.5 |
-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: 2G01 解像度: 3→19.97 Å / Rfactor Rfree error: 0.005 / Data cutoff high absF: 419658.34 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / 交差検証法: THROUGHOUT / σ(F): 2 詳細: Due to a feature in the refinement program, the structure was refined with OXT on one or more residues that is not the terminal residue of the sequence. In all these instances the OXT was ...詳細: Due to a feature in the refinement program, the structure was refined with OXT on one or more residues that is not the terminal residue of the sequence. In all these instances the OXT was changed to N of the next residue. THE AUTHOR STATES: ALTHOUGH THE DATA IN THE HIGHEST RESOLUTION SHELL HAD POOR AGREEMENT FACTOR, IT WAS DECIDED TO INCLUDE THEM IN THE REFINEMENT BECAUSE THEY WERE RELATIVELY STRONG FOR THESE WEAK-DIFFRACTING CRYSTALS AND TO ADD MORE DATA GIVEN THE LARGE NUMBER OF ATOMS IN THE ASYMMETRIC UNIT. THE REFINEMENT OF INDIVIDUAL, RESTRAINT, B-FACTORS DROPPED BOTH THE R- AND THE R-FREE AND SO IT WAS CONSIDERED TO BE REASONABLE. HOWEVER, THE INDIVIDUAL VALUES REFLECT MORE TRENDS THAN INDIVIDUAL DIFFERENCES. THEY HAVE BEEN RETAINED IN THE ENTRY SPECIALLY TO SHOW DIFFERENCES BETWEEN THE SO4 IONS AND LIGANDS, AND AMONG DIFFERENT AMINO ACIDS IN THE CHAIN. THE DIFFERENCES AMONG INDIVDUAL ATOMS/GROUPS WITHIN EACH RESIDUE SHOULD BE CONSIDERED ONLY AS A TREND.
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溶媒の処理 | 溶媒モデル: FLAT MODEL / Bsol: 25.0512 Å2 / ksol: 0.29954 e/Å3 | |||||||||||||||||||||||||
原子変位パラメータ | Biso mean: 59.4 Å2
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Refine analyze |
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精密化ステップ | サイクル: LAST / 解像度: 3→19.97 Å
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拘束条件 |
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LS精密化 シェル | 解像度: 3→3.11 Å / Rfactor Rfree error: 0.027 / Total num. of bins used: 10
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Xplor file |
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