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Yorodumi- PDB-6n3l: Identification of novel, potent and selective GCN2 inhibitors as ... -
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-Basic information
Entry | Database: PDB / ID: 6n3l | ||||||
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Title | Identification of novel, potent and selective GCN2 inhibitors as first-in-class anti-tumor agents | ||||||
Components | eIF-2-alpha kinase GCN2,eIF-2-alpha kinase GCN2 | ||||||
Keywords | transferase/transferase inhibitor / GCN2 / Kinase / Inhibitor / Anti-tumor / transferase-transferase inhibitor complex | ||||||
Function / homology | Function and homology information positive regulation of translational initiation in response to starvation / negative regulation of cytoplasmic translational initiation in response to stress / negative regulation of CREB transcription factor activity / regulation of translational initiation by eIF2 alpha phosphorylation / eiF2alpha phosphorylation in response to endoplasmic reticulum stress / GCN2-mediated signaling / eukaryotic translation initiation factor 2alpha kinase activity / negative regulation of translational initiation in response to stress / negative regulation by host of viral genome replication / regulation of feeding behavior ...positive regulation of translational initiation in response to starvation / negative regulation of cytoplasmic translational initiation in response to stress / negative regulation of CREB transcription factor activity / regulation of translational initiation by eIF2 alpha phosphorylation / eiF2alpha phosphorylation in response to endoplasmic reticulum stress / GCN2-mediated signaling / eukaryotic translation initiation factor 2alpha kinase activity / negative regulation of translational initiation in response to stress / negative regulation by host of viral genome replication / regulation of feeding behavior / T cell activation involved in immune response / positive regulation of adaptive immune response / regulation of translational initiation / cellular response to cold / neuron projection extension / Response of EIF2AK4 (GCN2) to amino acid deficiency / negative regulation of neuron differentiation / long-term memory / cytosolic ribosome / negative regulation of translational initiation / positive regulation of defense response to virus by host / cellular response to amino acid starvation / DNA damage checkpoint signaling / learning / positive regulation of long-term synaptic potentiation / cellular response to UV / defense response to virus / viral translation / adaptive immune response / protein autophosphorylation / tRNA binding / non-specific serine/threonine protein kinase / cell cycle / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / ATP binding / nucleus / cytosol / cytoplasm Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.61 Å | ||||||
Authors | Hoffman, I.D. / Fujimoto, J. / Kurasawa, O. / Takagi, T. / Klein, M.G. / Kefala, G. / Ding, S.C. / Cary, D.R. / Mizojiri, R. | ||||||
Citation | Journal: Acs Med.Chem.Lett. / Year: 2019 Title: Identification of Novel, Potent, and Orally Available GCN2 Inhibitors with Type I Half Binding Mode. Authors: Fujimoto, J. / Kurasawa, O. / Takagi, T. / Liu, X. / Banno, H. / Kojima, T. / Asano, Y. / Nakamura, A. / Nambu, T. / Hata, A. / Ishii, T. / Sameshima, T. / Debori, Y. / Miyamoto, M. / Klein, ...Authors: Fujimoto, J. / Kurasawa, O. / Takagi, T. / Liu, X. / Banno, H. / Kojima, T. / Asano, Y. / Nakamura, A. / Nambu, T. / Hata, A. / Ishii, T. / Sameshima, T. / Debori, Y. / Miyamoto, M. / Klein, M.G. / Tjhen, R. / Sang, B.C. / Levin, I. / Lane, S.W. / Snell, G.P. / Li, K. / Kefala, G. / Hoffman, I.D. / Ding, S.C. / Cary, D.R. / Mizojiri, R. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 6n3l.cif.gz | 212.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6n3l.ent.gz | 169.8 KB | Display | PDB format |
PDBx/mmJSON format | 6n3l.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/n3/6n3l ftp://data.pdbj.org/pub/pdb/validation_reports/n3/6n3l | HTTPS FTP |
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-Related structure data
-Links
-Assembly
Deposited unit |
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1 |
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2 |
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Unit cell |
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Noncrystallographic symmetry (NCS) | NCS domain:
NCS domain segments: Component-ID: 0 / Ens-ID: 1 / Beg auth comp-ID: SER / Beg label comp-ID: SER / End auth comp-ID: PRO / End label comp-ID: PRO / Refine code: 0 / Auth seq-ID: 584 - 1002 / Label seq-ID: 24 - 319
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-Components
#1: Protein | Mass: 37850.621 Da / Num. of mol.: 2 Mutation: D848N, T899A, T904A, K807A,D848N, T899A, T904A, K807A Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: EIF2AK4, GCN2, KIAA1338 / Cell line (production host): Sf9 / Production host: unidentified baculovirus References: UniProt: Q9P2K8, non-specific serine/threonine protein kinase #2: Chemical | #3: Water | ChemComp-HOH / | |
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-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 2.22 Å3/Da / Density % sol: 39.8 % |
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Crystal grow | Temperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.5 Details: 100 mM Tris 8.5, 24% PEG3350, 450 mM NaFormate, 1% hexanediol |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Diffraction source | Source: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.97648 Å | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Detector | Type: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 24, 2014 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Radiation wavelength | Wavelength: 0.97648 Å / Relative weight: 1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reflection | Resolution: 2.6→50 Å / Num. obs: 36200 / % possible obs: 99.5 % / Redundancy: 3.7 % / Rmerge(I) obs: 0.117 / Rpim(I) all: 0.071 / Rrim(I) all: 0.133 / Χ2: 1.015 / Net I/σ(I): 8 / Num. measured all: 132879 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reflection shell | Diffraction-ID: 1
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-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.61→25 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.904 / SU B: 37.065 / SU ML: 0.34 / SU R Cruickshank DPI: 0.8171 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.817 / ESU R Free: 0.364 Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
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Solvent computation | Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso max: 181.19 Å2 / Biso mean: 59.547 Å2 / Biso min: 32.49 Å2
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Refinement step | Cycle: final / Resolution: 2.61→25 Å
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Refine LS restraints |
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Refine LS restraints NCS | Ens-ID: 1 / Number: 7259 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.1 Å / Weight position: 0.05
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LS refinement shell | Resolution: 2.611→2.678 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
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Refinement TLS params. | Method: refined / Refine-ID: X-RAY DIFFRACTION
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Refinement TLS group |
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