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- PDB-6n3o: Identification of novel, potent and selective GCN2 inhibitors as ... -

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Basic information

Entry
Database: PDB / ID: 6n3o
TitleIdentification of novel, potent and selective GCN2 inhibitors as first-in-class anti-tumor agents
ComponentseIF-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 / 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 / positive regulation of adaptive immune response / T cell activation involved in 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 / positive regulation of defense response to virus by host / negative regulation of translational initiation / cytosolic ribosome / 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 / protein autophosphorylation / adaptive immune response / tRNA binding / non-specific serine/threonine protein kinase / 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 profile. / RWD / RWD domain / Class II Histidinyl-tRNA synthetase (HisRS)-like catalytic core domain / Histidyl-tRNA synthetase / : ...eIF-2-alpha kinase Gcn2 / Histidyl tRNA synthetase-related domain / Anticodon binding domain of tRNAs / RWD domain / RWD domain profile. / RWD / RWD domain / 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-KA7 / eIF-2-alpha kinase GCN2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)36,6642
Polymers36,2121
Non-polymers4521
Water30617
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)82.899, 82.899, 193.702
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 / 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-KA7 / N-{3-[(2-aminopyrimidin-5-yl)ethynyl]-2,4-difluorophenyl}-5-chloro-2-methoxypyridine-3-sulfonamide


Mass: 451.834 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H12ClF2N5O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 17 / Source method: isolated from a natural source / Formula: H2O

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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: 2.65 Å3/Da / Density % sol: 53.64 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 100 mM Na Citrate pH 5.6, 8% PEG 6K, 0.7 M LiCl, 1% 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: Apr 8, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.4→48.43 Å / Num. obs: 16229 / % possible obs: 100 % / Redundancy: 18.6 % / CC1/2: 1 / Rmerge(I) obs: 0.099 / Rpim(I) all: 0.023 / Rrim(I) all: 0.102 / Net I/σ(I): 23.1
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
2.4-2.4919.63.62116560.460.8313.716100
8.98-48.4313.50.02339910.0060.02399.5

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Processing

Software
NameVersionClassification
REFMACrefinement
HKL-2000data scaling
PDB_EXTRACT3.24data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.4→25 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.928 / WRfactor Rfree: 0.2305 / WRfactor Rwork: 0.1757 / FOM work R set: 0.762 / SU B: 21.225 / SU ML: 0.214 / SU R Cruickshank DPI: 0.27 / SU Rfree: 0.2308 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.27 / ESU R Free: 0.231 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2544 796 4.9 %RANDOM
Rwork0.1992 ---
obs0.202 15338 99.78 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 198.82 Å2 / Biso mean: 84.3 Å2 / Biso min: 46.31 Å2
Baniso -1Baniso -2Baniso -3
1-0.65 Å20.32 Å20 Å2
2--0.65 Å20 Å2
3----2.1 Å2
Refinement stepCycle: final / Resolution: 2.4→25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2069 0 30 17 2116
Biso mean--57.45 67.16 -
Num. residues----252
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0132152
X-RAY DIFFRACTIONr_bond_other_d0.0010.0171973
X-RAY DIFFRACTIONr_angle_refined_deg1.4361.6632913
X-RAY DIFFRACTIONr_angle_other_deg1.1441.5764568
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5895248
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.08421.626123
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.01315367
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.3681516
X-RAY DIFFRACTIONr_chiral_restr0.0580.2267
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.022413
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02471
LS refinement shellResolution: 2.4→2.462 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.361 52 -
Rwork0.368 1095 -
all-1147 -
obs--100 %
Refinement TLS params.Method: refined / Origin x: -7.0846 Å / Origin y: -24.2042 Å / Origin z: 12.7871 Å
111213212223313233
T0.1766 Å20.1445 Å20.0016 Å2-0.1656 Å2-0.0026 Å2--0.3096 Å2
L1.9288 °20.5488 °20.1926 °2-6.6412 °20.3658 °2--2.8924 °2
S-0.0628 Å °0.0706 Å °-0.708 Å °-0.3968 Å °0.1269 Å °0.3566 Å °0.2829 Å °0.19 Å °-0.0642 Å °

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