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- PDB-4x7h: Co-crystal Structure of PERK bound to N-{5-[(6,7-dimethoxyquinoli... -

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Basic information

Entry
Database: PDB / ID: 4x7h
TitleCo-crystal Structure of PERK bound to N-{5-[(6,7-dimethoxyquinolin-4-yl)oxy]pyridin-2-yl}-1-methyl-3-oxo-2-phenyl-5-(pyridin-4-yl)-2,3-dihydro-1H-pyrazole-4-carboxamide 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 / negative regulation of translation in response to stress / regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / regulation of translational initiation by eIF2 alpha phosphorylation / eiF2alpha phosphorylation in response to endoplasmic reticulum stress / chondrocyte development / eukaryotic translation initiation factor 2alpha kinase activity / response to manganese-induced endoplasmic reticulum stress / negative regulation of translational initiation in response to stress / PERK-mediated unfolded protein response ...regulation of endoplasmic reticulum stress-induced eIF2 alpha phosphorylation / negative regulation of translation in response to stress / regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / regulation of translational initiation by eIF2 alpha phosphorylation / eiF2alpha phosphorylation in response to endoplasmic reticulum stress / chondrocyte development / eukaryotic translation initiation factor 2alpha kinase activity / response to manganese-induced endoplasmic reticulum stress / negative regulation of translational initiation in response to stress / PERK-mediated unfolded protein response / PERK regulates gene expression / negative regulation of myelination / endocrine pancreas development / ALK mutants bind TKIs / endoplasmic reticulum organization / cellular response to cold / positive regulation of transcription by RNA polymerase I / ER overload response / bone mineralization / Signaling by ALK fusions and activated point mutants / positive regulation of vascular endothelial growth factor production / cellular response to glucose starvation / endoplasmic reticulum unfolded protein response / negative regulation of translational initiation / cellular response to amino acid starvation / response to endoplasmic reticulum stress / ossification / insulin-like growth factor receptor signaling pathway / skeletal system development / calcium-mediated signaling / Hsp90 protein binding / positive regulation of protein localization to nucleus / activation of cysteine-type endopeptidase activity involved in apoptotic process / KEAP1-NFE2L2 pathway / protein phosphatase binding / peptidyl-serine phosphorylation / angiogenesis / negative regulation of translation / protein autophosphorylation / non-specific serine/threonine protein kinase / protein kinase activity / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / endoplasmic reticulum membrane / positive regulation of gene expression / perinuclear region of cytoplasm / enzyme binding / endoplasmic reticulum / ATP binding / membrane / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Quinoprotein alcohol dehydrogenase-like superfamily / 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. / WD40/YVTN repeat-like-containing domain superfamily / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain ...Quinoprotein alcohol dehydrogenase-like superfamily / 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. / WD40/YVTN repeat-like-containing domain superfamily / 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-3Z2 / Eukaryotic translation initiation factor 2-alpha kinase 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsShaffer, P.L. / Bellon, S.F. / 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 1.0Feb 4, 2015Provider: repository / Type: Initial release
Revision 1.1Feb 25, 2015Group: Database references
Revision 1.2Nov 22, 2017Group: Database references / Derived calculations ...Database references / Derived calculations / Refinement description / Source and taxonomy / Structure summary
Category: citation / entity_src_gen ...citation / entity_src_gen / pdbx_struct_assembly / pdbx_struct_assembly_prop / pdbx_struct_oper_list / software / struct_keywords
Item: _citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag ..._citation.journal_id_CSD / _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 / _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)37,5834
Polymers36,8161
Non-polymers7673
Water3,297183
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area310 Å2
ΔGint-19 kcal/mol
Surface area13450 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.428, 81.428, 127.933
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-1228-

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-3Z2 / N-{5-[(6,7-dimethoxyquinolin-4-yl)oxy]pyridin-2-yl}-1-methyl-3-oxo-2-phenyl-5-(pyridin-4-yl)-2,3-dihydro-1H-pyrazole-4-carboxamide


Mass: 574.586 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H26N6O5
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 183 / 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: 2.88 Å3/Da / Density % sol: 57.29 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5 / Details: 14% PEG 3350, 0.3M Sodium Sulfate, 0.1M BTP pH 6.5

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Data collection

DiffractionMean temperature: 80 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Aug 18, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. obs: 29688 / % possible obs: 100 % / Redundancy: 13.8 % / Rmerge(I) obs: 0.097 / Χ2: 1.131 / Net I/av σ(I): 26.938 / Net I/σ(I): 12.3 / Num. measured all: 410972
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Num. unique allΧ2% possible allRmerge(I) obs
2-2.0710.329100.832100
2.07-2.1514.329030.8011000.732
2.15-2.2514.629210.8521000.517
2.25-2.3714.629020.8881000.329
2.37-2.5214.529460.9651000.227
2.52-2.7114.529411.1491000.161
2.71-2.9914.429531.4061000.117
2.99-3.4214.229751.6291000.091
3.42-4.3113.930351.621000.089
4.31-5013.132021.07399.80.07

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Processing

Software
NameVersionClassification
REFMAC5.7.0029refinement
SCALEPACKdata scaling
PDB_EXTRACT3.15data extraction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1ZY4

1zy4


Resolution: 2→37.81 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.957 / SU B: 5.987 / SU ML: 0.088 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.147 / ESU R Free: 0.127 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2136 1500 5.1 %RANDOM
Rwork0.2014 28109 --
obs0.202 29674 99.75 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 88.54 Å2 / Biso mean: 45.115 Å2 / Biso min: 25.67 Å2
Baniso -1Baniso -2Baniso -3
1-0.78 Å20 Å20 Å2
2--0.78 Å2-0 Å2
3----1.57 Å2
Refinement stepCycle: final / Resolution: 2→37.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2084 0 53 183 2320
Biso mean--46.27 54.53 -
Num. residues----256
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0192266
X-RAY DIFFRACTIONr_angle_refined_deg1.1431.9973081
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.7475271
X-RAY DIFFRACTIONr_dihedral_angle_2_deg29.96324.037109
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.61815395
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.0421515
X-RAY DIFFRACTIONr_chiral_restr0.0970.2327
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0211753
LS refinement shellResolution: 2.003→2.055 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.26 107 -
Rwork0.254 1990 -
all-2097 -
obs--97.58 %
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)
11.31670.53320.09741.72010.13413.56120.0860.08970.29540.02590.01650.0392-0.5292-0.116-0.10240.12260.02260.04140.06680.03160.1271-21.491534.824129.2286
22.13610.39960.1221.0423-0.17134.21310.07010.1859-0.0639-0.0399-0.0587-0.1472-0.01060.3333-0.01140.01970.0299-0.00210.07890.00180.05144.383825.050125.346
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A584 - 889
2X-RAY DIFFRACTION2A890 - 1085

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