Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Structural insights into inhibitor regulation of the DNA repair protein DNA-PKcs.
Journal, issue, pages	Nature, Vol. 601, Issue 7894, Page 643-648, Year 2022
Publish date	Jan 5, 2022
Authors	Shikang Liang / Sherine E Thomas / Amanda K Chaplin / Steven W Hardwick / Dimitri Y Chirgadze / Tom L Blundell /
PubMed Abstract	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.
External links	Nature / PubMed:34987222 / PubMed Central
Methods	EM (single particle)
Resolution	2.96 - 4.3 Å
Structure data	13062 7otm EMDB-13062, PDB-7otm: Cryo-EM structure of DNA-PKcs in complex with NU7441 Method: EM (single particle) / Resolution: 3.33 Å 13064 7otp EMDB-13064, PDB-7otp: DNA-PKcs in complex with ATPgammaS-Mg Method: EM (single particle) / Resolution: 3.4 Å 13067 7otv EMDB-13067, PDB-7otv: DNA-PKcs in complex with wortmannin Method: EM (single particle) / Resolution: 3.24 Å 13068 7otw EMDB-13068, PDB-7otw: DNA-PKcs in complex with AZD7648 Method: EM (single particle) / Resolution: 2.99 Å 13069 7oty EMDB-13069, PDB-7oty: DNA-PKcs in complex with M3814 Method: EM (single particle) / Resolution: 2.96 Å EMDB-13443: DNA-PK in complex with ATPgammaS Method: EM (single particle) / Resolution: 4.3 Å
Chemicals	ChemComp-2R4: 8-(dibenzo[b,d]thiophen-4-yl)-2-(morpholin-4-yl)-4H-chromen-4-one ChemComp-AGS: PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / ATP-gamma-S, energy-carrying molecule analogueYM ChemComp-MG: Unknown entry 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, / inhibitorYM / 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
Source	homo sapiens (human) Human (human)
Keywords	DNA BINDING PROTEIN / complex / inhibitor / DNA repair