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	Structural insights into inhibitor regulation of the DNA repair protein DNA-PKcs.
ジャーナル・号・ページ	Nature, Vol. 601, Issue 7894, Page 643-648, Year 2022
掲載日	2022年1月5日
著者	Shikang Liang / Sherine E Thomas / Amanda K Chaplin / Steven W Hardwick / Dimitri Y Chirgadze / Tom L Blundell /
PubMed 要旨	The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) has a central role in non-homologous end joining, one of the two main pathways that detect and repair DNA double-strand breaks (DSBs) in ...The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) has a central role in non-homologous end joining, one of the two main pathways that detect and repair DNA double-strand breaks (DSBs) in humans. DNA-PKcs is of great importance in repairing pathological DSBs, making DNA-PKcs inhibitors attractive therapeutic agents for cancer in combination with DSB-inducing radiotherapy and chemotherapy. Many of the selective inhibitors of DNA-PKcs that have been developed exhibit potential as treatment for various cancers. Here we report cryo-electron microscopy (cryo-EM) structures of human DNA-PKcs natively purified from HeLa cell nuclear extracts, in complex with adenosine-5'-(γ-thio)-triphosphate (ATPγS) and four inhibitors (wortmannin, NU7441, AZD7648 and M3814), including drug candidates undergoing clinical trials. The structures reveal molecular details of ATP binding at the active site before catalysis and provide insights into the modes of action and specificities of the competitive inhibitors. Of note, binding of the ligands causes movement of the PIKK regulatory domain (PRD), revealing a connection between the p-loop and PRD conformations. Electrophoretic mobility shift assay and cryo-EM studies on the DNA-dependent protein kinase holoenzyme further show that ligand binding does not have a negative allosteric or inhibitory effect on assembly of the holoenzyme complex and that inhibitors function through direct competition with ATP. Overall, the structures described in this study should greatly assist future efforts in rational drug design targeting DNA-PKcs, demonstrating the potential of cryo-EM in structure-guided drug development for large and challenging targets.
リンク	Nature / PubMed:34987222 / PubMed Central
手法	EM (単粒子)
解像度	2.96 - 4.3 Å
構造データ	13062 7otm EMDB-13062, PDB-7otm: Cryo-EM structure of DNA-PKcs in complex with NU7441 手法: EM (単粒子) / 解像度: 3.33 Å 13064 7otp EMDB-13064, PDB-7otp: DNA-PKcs in complex with ATPgammaS-Mg 手法: EM (単粒子) / 解像度: 3.4 Å 13067 7otv EMDB-13067, PDB-7otv: DNA-PKcs in complex with wortmannin 手法: EM (単粒子) / 解像度: 3.24 Å 13068 7otw EMDB-13068, PDB-7otw: DNA-PKcs in complex with AZD7648 手法: EM (単粒子) / 解像度: 2.99 Å 13069 7oty EMDB-13069, PDB-7oty: DNA-PKcs in complex with M3814 手法: EM (単粒子) / 解像度: 2.96 Å EMDB-13443: DNA-PK in complex with ATPgammaS 手法: EM (単粒子) / 解像度: 4.3 Å
化合物	ChemComp-2R4: 8-(dibenzo[b,d]thiophen-4-yl)-2-(morpholin-4-yl)-4H-chromen-4-one / NU-7441 ChemComp-AGS: PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / ATP-γ-S / ATP-gamma-S, エネルギー貯蔵分子類似体YM ChemComp-MG: Unknown entry / マグネシウムジカチオン ChemComp-KWT: (1S,6BR,9AS,11R,11BR)-9A,11B-DIMETHYL-1-[(METHYLOXY)METHYL]-3,6,9-TRIOXO-1,6,6B,7,8,9,9A,10,11,11B-DECAHYDRO-3H-FURO[4, / ウォルトマンニン / 阻害剤YM / Wortmannin ChemComp-MBW: 7-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(oxan-4-yl)purin-8-one ChemComp-1IX: (~{S})-[2-chloranyl-4-fluoranyl-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)methanol
由来	homo sapiens (ヒト) Human (ヒト)
キーワード	DNA BINDING PROTEIN (DNA結合タンパク質) / complex / inhibitor (酵素阻害剤) / DNA repair (DNA修復)