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- PDB-4x7j: Co-crystal Structure of PERK with 2-amino-N-[4-methoxy-3-(trifluo... -

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Basic information

Entry
Database: PDB / ID: 4x7j
TitleCo-crystal Structure of PERK with 2-amino-N-[4-methoxy-3-(trifluoromethyl)phenyl]-4-methyl-3-[2-(methylamino)quinazolin-6-yl]benzamide inhibitor
ComponentsEukaryotic translation initiation factor 2-alpha kinase 3,Eukaryotic translation initiation factor 2-alpha kinase 3
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / CATALYTIC DOMAIN / TRANSFERASE-TRANSFERASE INHIBITOR / COMPLEX / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


regulation of endoplasmic reticulum stress-induced eIF2 alpha phosphorylation / regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / eiF2alpha phosphorylation in response to endoplasmic reticulum stress / regulation of translation initiation in response to endoplasmic reticulum stress / chondrocyte development / response to manganese-induced endoplasmic reticulum stress / negative regulation of translation in response to stress / negative regulation of translational initiation in response to stress / PERK-mediated unfolded protein response / negative regulation of myelination ...regulation of endoplasmic reticulum stress-induced eIF2 alpha phosphorylation / regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / eiF2alpha phosphorylation in response to endoplasmic reticulum stress / regulation of translation initiation in response to endoplasmic reticulum stress / chondrocyte development / response to manganese-induced endoplasmic reticulum stress / negative regulation of translation in response to stress / negative regulation of translational initiation in response to stress / PERK-mediated unfolded protein response / negative regulation of myelination / PERK regulates gene expression / mitochondria-associated endoplasmic reticulum membrane contact site / endocrine pancreas development / misfolded protein binding / ALK mutants bind TKIs / endoplasmic reticulum organization / regulation of translational initiation / Modulation of host responses by IFN-stimulated genes / cellular response to cold / ER overload response / bone mineralization / positive regulation of transcription by RNA polymerase I / positive regulation of vascular endothelial growth factor production / endoplasmic reticulum unfolded protein response / cellular response to glucose starvation / translation regulator activity / negative regulation of translational initiation / cellular response to amino acid starvation / ossification / insulin-like growth factor receptor signaling pathway / response to endoplasmic reticulum stress / skeletal system development / non-specific protein-tyrosine kinase / Hsp90 protein binding / calcium-mediated signaling / positive regulation of protein localization to nucleus / KEAP1-NFE2L2 pathway / Signaling by ALK fusions and activated point mutants / protein autophosphorylation / protein tyrosine kinase activity / protein phosphatase binding / angiogenesis / eukaryotic translation initiation factor 2alpha kinase activity / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / histone H3T11 kinase activity / histone H3T45 kinase activity / non-specific serine/threonine protein kinase / protein kinase activity / negative regulation of translation / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / positive regulation of gene expression / endoplasmic reticulum membrane / perinuclear region of cytoplasm / enzyme binding / endoplasmic reticulum / ATP binding / identical protein binding / nucleus / membrane / cytosol / cytoplasm
Similarity search - Function
: / Quinoprotein alcohol dehydrogenase-like superfamily / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain ...: / Quinoprotein alcohol dehydrogenase-like superfamily / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / WD40/YVTN repeat-like-containing domain superfamily / 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-3Z1 / L(+)-TARTARIC ACID / Eukaryotic translation initiation factor 2-alpha kinase 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsShaffer, P.L. / Long, A.M. / Chen, H.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Discovery of 1H-Pyrazol-3(2H)-ones as Potent and Selective Inhibitors of Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK).
Authors: Smith, A.L. / Andrews, K.L. / Beckmann, H. / Bellon, S.F. / Beltran, P.J. / Booker, S. / Chen, H. / Chung, Y.A. / D'Angelo, N.D. / Dao, J. / Dellamaggiore, K.R. / Jaeckel, P. / Kendall, R. / ...Authors: Smith, A.L. / Andrews, K.L. / Beckmann, H. / Bellon, S.F. / Beltran, P.J. / Booker, S. / Chen, H. / Chung, Y.A. / D'Angelo, N.D. / Dao, J. / Dellamaggiore, K.R. / Jaeckel, P. / Kendall, R. / Labitzke, K. / Long, A.M. / Materna-Reichelt, S. / Mitchell, P. / Norman, M.H. / Powers, D. / Rose, M. / Shaffer, P.L. / Wu, M.M. / Lipford, J.R.
History
DepositionDec 9, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 28, 2015Provider: repository / Type: Initial release
Revision 1.1Feb 25, 2015Group: Database references
Revision 1.2Sep 27, 2017Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Source and taxonomy / Structure summary
Category: citation / diffrn_detector ...citation / diffrn_detector / entity_src_gen / pdbx_struct_assembly / pdbx_struct_assembly_prop / pdbx_struct_oper_list / software / struct_keywords
Item: _citation.journal_id_CSD / _diffrn_detector.detector ..._citation.journal_id_CSD / _diffrn_detector.detector / _entity_src_gen.pdbx_alt_source_flag / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_assembly_prop.type / _pdbx_struct_assembly_prop.value / _pdbx_struct_oper_list.symmetry_operation / _software.classification / _struct_keywords.text
Revision 1.3Sep 27, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
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: Eukaryotic translation initiation factor 2-alpha kinase 3,Eukaryotic translation initiation factor 2-alpha kinase 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,4483
Polymers36,8161
Non-polymers6322
Water1,910106
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area200 Å2
ΔGint0 kcal/mol
Surface area13430 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.020, 81.020, 127.617
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212
Components on special symmetry positions
IDModelComponents
11A-1217-

HOH

21A-1236-

HOH

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Components

#1: Protein Eukaryotic translation initiation factor 2-alpha kinase 3,Eukaryotic translation initiation factor 2-alpha kinase 3 / PRKR-like endoplasmic reticulum kinase / Pancreatic eIF2-alpha kinase / HsPEK


Mass: 36816.363 Da / Num. of mol.: 1 / Mutation: D937N, Deletion of 670-874
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EIF2AK3, PEK, PERK / Production host: Escherichia coli (E. coli)
References: UniProt: Q9NZJ5, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-3Z1 / 2-amino-N-[4-methoxy-3-(trifluoromethyl)phenyl]-4-methyl-3-[2-(methylamino)quinazolin-6-yl]benzamide


Mass: 481.470 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H22F3N5O2
#3: Chemical ChemComp-TLA / L(+)-TARTARIC ACID


Mass: 150.087 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H6O6
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 106 / 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: 2.84 Å3/Da / Density % sol: 56.75 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 0.6M Na/K Tartrate

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Data collection

DiffractionMean temperature: 80 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: MAR scanner 300 mm plate / Detector: IMAGE PLATE / Date: Jun 22, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.3→50 Å / Num. obs: 19528 / % possible obs: 99.6 % / Redundancy: 5.5 % / Rmerge(I) obs: 0.067 / Χ2: 1.234 / Net I/av σ(I): 21.962 / Net I/σ(I): 13.1 / Num. measured all: 108208
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2.3-2.385.40.55219351.1399.8
2.38-2.485.80.43418911.16999.9
2.48-2.595.60.31519151.232100
2.59-2.735.70.22219291.252100
2.73-2.95.70.15919231.34799.9
2.9-3.125.60.10619551.369100
3.12-3.445.60.07819371.27100
3.44-3.935.50.05419671.2899.8
3.93-4.955.30.05119861.09499.4
4.95-505.20.03920901.18397.1

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
REFMAC5.7.0029refinement
PDB_EXTRACT3.15data extraction
HKL-2000data scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4X7H

4x7h


Resolution: 2.3→42.64 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.944 / SU B: 10.677 / SU ML: 0.135 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.224 / ESU R Free: 0.185 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2251 1001 5.1 %RANDOM
Rwork0.1949 18477 --
obs0.1964 -99.43 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 94.02 Å2 / Biso mean: 50.066 Å2 / Biso min: 29.26 Å2
Baniso -1Baniso -2Baniso -3
1--1.03 Å2-0 Å2-0 Å2
2---1.03 Å20 Å2
3---2.06 Å2
Refinement stepCycle: final / Resolution: 2.3→42.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2093 0 45 106 2244
Biso mean--45.88 52.73 -
Num. residues----257
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0192217
X-RAY DIFFRACTIONr_angle_refined_deg0.9641.9913004
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.6495262
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.18723.619105
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.66415391
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.2431516
X-RAY DIFFRACTIONr_chiral_restr0.0730.2322
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0211692
LS refinement shellResolution: 2.299→2.359 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.319 61 -
Rwork0.254 1318 -
all-1379 -
obs--97.73 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.5626-0.16940.02210.9357-0.16392.06330.1051-0.0537-0.133-0.04230.01490.02250.2378-0.1413-0.120.3251-0.0346-0.04570.26870.03110.06419.1466.0743.073
21.8671-0.172-0.240.0909-0.34082.52750.0994-0.1361-0.00250.0099-0.1197-0.0001-0.0130.34530.02030.2617-0.0271-0.00030.3721-0.00730.001344.89515.4826.603
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A584 - 889
2X-RAY DIFFRACTION2A890 - 1085

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