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データを開く
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基本情報
登録情報 | データベース: PDB / ID: 7l28 | ||||||
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タイトル | Crystal structure of the catalytic domain of human PDE3A bound to Trequinsin | ||||||
![]() | cGMP-inhibited 3',5'-cyclic phosphodiesterase A | ||||||
![]() | HYDROLASE/HYDROLASE INHIBITOR / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex | ||||||
機能・相同性 | ![]() 3',5'-cGMP-inhibited cyclic-nucleotide phosphodiesterase activity / estrogen binding / regulation of ribonuclease activity / positive regulation of oocyte development / regulation of meiotic nuclear division / cellular response to cGMP / negative regulation of cAMP-mediated signaling / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of vascular permeability / negative regulation of vascular permeability ...3',5'-cGMP-inhibited cyclic-nucleotide phosphodiesterase activity / estrogen binding / regulation of ribonuclease activity / positive regulation of oocyte development / regulation of meiotic nuclear division / cellular response to cGMP / negative regulation of cAMP-mediated signaling / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of vascular permeability / negative regulation of vascular permeability / oocyte maturation / 3',5'-cyclic-nucleotide phosphodiesterase / cGMP-mediated signaling / nuclear estrogen receptor activity / 3',5'-cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / cellular response to transforming growth factor beta stimulus / cAMP-mediated signaling / apoptotic signaling pathway / lipid metabolic process / G alpha (s) signalling events / response to xenobiotic stimulus / G protein-coupled receptor signaling pathway / negative regulation of apoptotic process / membrane / metal ion binding / cytosol 類似検索 - 分子機能 | ||||||
生物種 | ![]() | ||||||
手法 | ![]() ![]() ![]() | ||||||
![]() | Horner, S.W. / Garvie, C. | ||||||
![]() | ![]() タイトル: Structure of PDE3A-SLFN12 complex reveals requirements for activation of SLFN12 RNase. 著者: Colin W Garvie / Xiaoyun Wu / Malvina Papanastasiou / Sooncheol Lee / James Fuller / Gavin R Schnitzler / Steven W Horner / Andrew Baker / Terry Zhang / James P Mullahoo / Lindsay Westlake / ...著者: Colin W Garvie / Xiaoyun Wu / Malvina Papanastasiou / Sooncheol Lee / James Fuller / Gavin R Schnitzler / Steven W Horner / Andrew Baker / Terry Zhang / James P Mullahoo / Lindsay Westlake / Stephanie H Hoyt / Marcus Toetzl / Matthew J Ranaghan / Luc de Waal / Joseph McGaunn / Bethany Kaplan / Federica Piccioni / Xiaoping Yang / Martin Lange / Adrian Tersteegen / Donald Raymond / Timothy A Lewis / Steven A Carr / Andrew D Cherniack / Christopher T Lemke / Matthew Meyerson / Heidi Greulich / ![]() ![]() 要旨: DNMDP and related compounds, or velcrins, induce complex formation between the phosphodiesterase PDE3A and the SLFN12 protein, leading to a cytotoxic response in cancer cells that express elevated ...DNMDP and related compounds, or velcrins, induce complex formation between the phosphodiesterase PDE3A and the SLFN12 protein, leading to a cytotoxic response in cancer cells that express elevated levels of both proteins. The mechanisms by which velcrins induce complex formation, and how the PDE3A-SLFN12 complex causes cancer cell death, are not fully understood. Here, we show that PDE3A and SLFN12 form a heterotetramer stabilized by binding of DNMDP. Interactions between the C-terminal alpha helix of SLFN12 and residues near the active site of PDE3A are required for complex formation, and are further stabilized by interactions between SLFN12 and DNMDP. Moreover, we demonstrate that SLFN12 is an RNase, that PDE3A binding increases SLFN12 RNase activity, and that SLFN12 RNase activity is required for DNMDP response. This new mechanistic understanding will facilitate development of velcrin compounds into new cancer therapies. | ||||||
履歴 |
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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 | ![]() | 309.2 KB | 表示 | ![]() |
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PDB形式 | ![]() | 249.3 KB | 表示 | ![]() |
PDBx/mmJSON形式 | ![]() | ツリー表示 | ![]() | |
その他 | ![]() |
-検証レポート
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
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-関連構造データ
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リンク
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集合体
登録構造単位 | ![]()
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単位格子 |
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非結晶学的対称性 (NCS) | NCSドメイン:
NCSドメイン領域: Component-ID: _ / Beg auth comp-ID: LYS / Beg label comp-ID: LYS / Refine code: _
NCSアンサンブル:
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要素
-タンパク質 , 1種, 4分子 ABCD
#1: タンパク質 | 分子量: 43169.121 Da / 分子数: 4 / 断片: Catalytic domain / 由来タイプ: 組換発現 詳細: N-terminal glycine from cleavage with TEV protease. Residues 780 to 800 replaced with GGSGGS linker. Residues 1029 to 1067 replaced with GGSGGS linker. 由来: (組換発現) ![]() ![]() ![]() 参照: UniProt: Q14432, 3',5'-cyclic-nucleotide phosphodiesterase |
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-非ポリマー , 5種, 123分子 ![](data/chem/img/XKG.gif)
![](data/chem/img/MN.gif)
![](data/chem/img/MG.gif)
![](data/chem/img/ACT.gif)
![](data/chem/img/HOH.gif)
![](data/chem/img/MN.gif)
![](data/chem/img/MG.gif)
![](data/chem/img/ACT.gif)
![](data/chem/img/HOH.gif)
#2: 化合物 | ChemComp-XKG / ( #3: 化合物 | ChemComp-MN / #4: 化合物 | ChemComp-MG / #5: 化合物 | ChemComp-ACT / #6: 水 | ChemComp-HOH / | |
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-詳細
研究の焦点であるリガンドがあるか | Y |
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-実験情報
-実験
実験 | 手法: ![]() |
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試料調製
結晶 | マシュー密度: 2.27 Å3/Da / 溶媒含有率: 45.91 % |
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結晶化 | 温度: 293.15 K / 手法: 蒸気拡散法, ハンギングドロップ法 / pH: 5.9 / 詳細: MES, PEG 3350, calcium acetate / PH範囲: 5.7 - 6.1 |
-データ収集
回折 | 平均測定温度: 100 K / Serial crystal experiment: N | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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放射光源 | 由来: ![]() ![]() ![]() | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
検出器 | タイプ: DECTRIS PILATUS3 S 6M / 検出器: PIXEL / 日付: 2018年7月26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: 0.976251 Å / 相対比: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
反射 | 解像度: 2.2→46.29 Å / Num. obs: 77869 / % possible obs: 98.2 % / 冗長度: 3.293 % / Biso Wilson estimate: 55.784 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.045 / Rrim(I) all: 0.054 / Χ2: 1.003 / Net I/σ(I): 14.54 / Num. measured all: 256435 / Scaling rejects: 147 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
反射 シェル | Diffraction-ID: 1
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解析
ソフトウェア |
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精密化 | 構造決定の手法: ![]() 開始モデル: 1SO2 解像度: 2.2→46.29 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.934 / 交差検証法: THROUGHOUT / σ(F): 0 / ESU R: 0.364 / ESU R Free: 0.24 / 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 : REFINED INDIVIDUALLY
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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 max: 147.79 Å2 / Biso mean: 59.439 Å2 / Biso min: 30 Å2
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精密化ステップ | サイクル: final / 解像度: 2.2→46.29 Å
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拘束条件 |
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Refine LS restraints NCS | Refine-ID: X-RAY DIFFRACTION / タイプ: interatomic distance / Weight position: 0.05
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LS精密化 シェル | 解像度: 2.204→2.261 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
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