EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	Structure of PDE3A-SLFN12 complex reveals requirements for activation of SLFN12 RNase.
ジャーナル・号・ページ	Nat Commun, Vol. 12, Issue 1, Page 4375, Year 2021
掲載日	2021年7月16日
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 /
PubMed 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.
リンク	Nat Commun / PubMed:34272366 / PubMed Central
手法	EM (単粒子) / X線回折
解像度	1.7 - 3.22 Å
構造データ	23494 7lrc EMDB-23494, PDB-7lrc: Cryo-EM of the SLFN12-PDE3A complex: PDE3A body refinement 手法: EM (単粒子) / 解像度: 2.97 Å 23495 7lrd EMDB-23495, PDB-7lrd: Cryo-EM of the SLFN12-PDE3A complex: Consensus subset model 手法: EM (単粒子) / 解像度: 3.22 Å 23496 7lre EMDB-23496, PDB-7lre: Cryo-EM of the SLFN12-PDE3A complex: SLFN12 body refinement 手法: EM (単粒子) / 解像度: 2.76 Å PDB-7kwe: Crystal structure of the catalytic domain of human PDE3A bound to DNMDP 手法: X-RAY DIFFRACTION / 解像度: 2.0 Å PDB-7l27: Crystal structure of the catalytic domain of human PDE3A 手法: X-RAY DIFFRACTION / 解像度: 1.7 Å PDB-7l28: Crystal structure of the catalytic domain of human PDE3A bound to Trequinsin 手法: X-RAY DIFFRACTION / 解像度: 2.2 Å PDB-7l29: Crystal structure of the catalytic domain of human PDE3A bound to AMP 手法: X-RAY DIFFRACTION / 解像度: 2.08 Å
化合物	ChemComp-X5M: (4~{R})-3-[4-(diethylamino)-3-[oxidanyl(oxidanylidene)-$l^{4}-azanyl]phenyl]-4-methyl-4,5-dihydro-1~{H}-pyridazin-6-one ChemComp-MN: Unknown entry ChemComp-MG: Unknown entry / マグネシウムジカチオン ChemComp-ACT: ACETATE ION / 酢酸イオン / 酢酸塩 ChemComp-HOH: WATER / 水 ChemComp-CA: Unknown entry / カルシウムジカチオン ChemComp-XKG: (2E)-9,10-dimethoxy-3-methyl-2-[(2,4,6-trimethylphenyl)imino]-2,3,6,7-tetrahydro-4H-pyrimido[6,1-a]isoquinolin-4-one / トレキンシン / 阻害剤YM / Trequinsin ChemComp-AMP: ADENOSINE MONOPHOSPHATE / AMP / AMPYM / アデニル酸 ChemComp-ZN: Unknown entry
由来	homo sapiens (ヒト)
キーワード	HYDROLASE (加水分解酵素) / HYDROLASE/HYDROLASE INHIBITOR / HYDROLASE-HYDROLASE INHIBITOR complex / complex / velcrin / molecular glue / DNMDP / RNA BINDING PROTEIN (RNA結合タンパク質)