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- PDB-6n3n: Identification of novel, potent and selective GCN2 inhibitors as ... -

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Basic information

Entry
Database: PDB / ID: 6n3n
TitleIdentification of novel, potent and selective GCN2 inhibitors as first-in-class anti-tumor agents
ComponentseIF-2-alpha kinase GCN2,eIF-2-alpha kinase GCN2
Keywordstransferase/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 / cellular response to leucine starvation / negative regulation by host of viral genome replication ...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 / cellular response to leucine starvation / 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 / negative regulation of translational initiation / positive regulation of defense response to virus by host / cellular response to amino acid starvation / cytosolic ribosome / DNA damage checkpoint signaling / learning / positive regulation of long-term synaptic potentiation / cellular response to UV / defense response to virus / viral translation / tRNA binding / adaptive immune response / protein autophosphorylation / 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
eIF-2-alpha kinase Gcn2 / Histidyl tRNA synthetase-related domain / Anticodon binding domain of tRNAs / RWD domain / RWD domain / RWD domain profile. / RWD / Class II Histidinyl-tRNA synthetase (HisRS)-like catalytic core domain / Histidyl-tRNA synthetase / Anticodon-binding domain superfamily ...eIF-2-alpha kinase Gcn2 / Histidyl tRNA synthetase-related domain / Anticodon binding domain of tRNAs / RWD domain / RWD domain / RWD domain profile. / RWD / Class II Histidinyl-tRNA synthetase (HisRS)-like catalytic core domain / Histidyl-tRNA synthetase / Anticodon-binding domain superfamily / Ubiquitin-conjugating enzyme/RWD-like / Class II Aminoacyl-tRNA synthetase/Biotinyl protein ligase (BPL) and lipoyl protein ligase (LPL) / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-KA4 / eIF-2-alpha kinase GCN2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.01 Å
AuthorsHoffman, I.D. / Fujimoto, J. / Kurasawa, O. / Takagi, T. / Klein, M.G. / Kefala, G. / Ding, S.C. / Cary, D.R. / Mizojiri, R.
CitationJournal: 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
DepositionNov 15, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 9, 2019Provider: repository / Type: Initial release
Revision 1.1Oct 30, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: eIF-2-alpha kinase GCN2,eIF-2-alpha kinase GCN2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,6972
Polymers36,2121
Non-polymers4851
Water0
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)82.117, 82.117, 192.551
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122

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Components

#1: Protein eIF-2-alpha kinase GCN2,eIF-2-alpha kinase GCN2 / Eukaryotic translation initiation factor 2-alpha kinase 4 / GCN2-like protein


Mass: 36211.773 Da / Num. of mol.: 1 / Mutation: 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 ChemComp-KA4 / N-{3-[(2-aminopyrimidin-5-yl)ethynyl]-2,4-difluorophenyl}-2,5-dichloro-3-(hydroxymethyl)benzene-1-sulfonamide


Mass: 485.291 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H12Cl2F2N4O3S / Feature type: SUBJECT OF INVESTIGATION

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.59 Å3/Da / Density % sol: 52.47 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 100 mM Na Citrate pH 5.6, 10% PEG 5K MME, 0.7 M LiCl, 3% Ethylene Glycol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Mar 31, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3→50 Å / Num. obs: 8173 / % possible obs: 99.1 % / Redundancy: 7.7 % / Rmerge(I) obs: 0.074 / Rpim(I) all: 0.029 / Rrim(I) all: 0.08 / Χ2: 1.007 / Net I/σ(I): 11.7
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
3-3.058.21.2983990.5040.4761.3850.96799.8
3.05-3.118.21.0383850.680.3831.1090.97799.7
3.11-3.178.20.9014010.8380.330.9621.00599.8
3.17-3.238.10.7323940.8520.270.7821.015100
3.23-3.380.5373950.890.1990.5741.031100
3.3-3.387.90.4194030.9540.1570.4481.00799.5
3.38-3.467.40.3383920.9470.1310.3641.04699.5
3.46-3.567.80.2594120.9760.0980.278199.5
3.56-3.667.60.2153900.9760.0820.231.08299.7
3.66-3.788.10.1633940.9890.060.1740.99299.5
3.78-3.918.20.1554090.9920.0570.1661.04499.5
3.91-4.078.10.1184030.9920.0430.1251.00499.8
4.07-4.267.80.0994140.9940.0370.1060.99499.5
4.26-4.487.30.0853970.9950.0340.0910.99799.2
4.48-4.767.30.0794190.9950.0310.085199.1
4.76-5.137.50.084120.9940.0310.0861.00398.8
5.13-5.647.70.0724080.9950.0270.0770.99598.8
5.64-6.467.30.0694290.9970.0270.0741.01199.1
6.46-8.136.80.0584390.9970.0230.0620.99398.4
8.13-506.30.0444780.9980.0190.0480.98894.5

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Processing

Software
NameVersionClassification
HKL-2000data scaling
REFMACrefinement
PDB_EXTRACT3.24data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.01→30 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.875 / SU B: 51.374 / SU ML: 0.398 / SU R Cruickshank DPI: 0.3917 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.434
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2772 408 5 %RANDOM
Rwork0.216 ---
obs0.2189 7751 99.44 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 238.29 Å2 / Biso mean: 128.887 Å2 / Biso min: 83.75 Å2
Baniso -1Baniso -2Baniso -3
1-0.68 Å20.34 Å20 Å2
2--0.68 Å2-0 Å2
3----2.2 Å2
Refinement stepCycle: final / Resolution: 3.01→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1984 0 31 0 2015
Biso mean--103.02 --
Num. residues----242
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0132063
X-RAY DIFFRACTIONr_bond_other_d0.0010.0171911
X-RAY DIFFRACTIONr_angle_refined_deg1.4061.6642790
X-RAY DIFFRACTIONr_angle_other_deg1.0971.5764420
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.1675236
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.02821.565115
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.58915355
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.5291515
X-RAY DIFFRACTIONr_chiral_restr0.0560.2258
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.022247
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02446
LS refinement shellResolution: 3.01→3.087 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.375 34 -
Rwork0.311 542 -
all-576 -
obs--98.97 %
Refinement TLS params.Method: refined / Origin x: -7.4652 Å / Origin y: -23.9887 Å / Origin z: 12.6473 Å
111213212223313233
T0.1527 Å20.1281 Å2-0.0379 Å2-0.1888 Å20.0785 Å2--0.4587 Å2
L2.4492 °21.3216 °20.0997 °2-8.5667 °21.3345 °2--3.6861 °2
S-0.0651 Å °-0.1254 Å °-0.8934 Å °-0.5111 Å °0.179 Å °0.4248 Å °0.0645 Å °0.2482 Å °-0.1139 Å °

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