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- PDB-4x7k: Co-crystal Structure of PERK bound to 4-{2-amino-3-[5-fluoro-2-(m... -

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Basic information

Entry
Database: PDB / ID: 4x7k
TitleCo-crystal Structure of PERK bound to 4-{2-amino-3-[5-fluoro-2-(methylamino)quinazolin-6-yl]-4-methylbenzoyl}-1-methyl-2,5-diphenyl-1,2-dihydro-3H-pyrazol-3-one 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 / endocrine pancreas development / negative regulation of myelination / PERK regulates gene expression / ALK mutants bind TKIs / endoplasmic reticulum organization / cellular response to cold / positive regulation of transcription by RNA polymerase I / bone mineralization / ER overload response / positive regulation of vascular endothelial growth factor production / cellular response to glucose starvation / endoplasmic reticulum unfolded protein response / negative regulation of translational initiation / response to endoplasmic reticulum stress / cellular response to amino acid starvation / ossification / insulin-like growth factor receptor signaling pathway / skeletal system development / calcium-mediated signaling / Hsp90 protein binding / : / positive regulation of protein localization to nucleus / KEAP1-NFE2L2 pathway / Signaling by ALK fusions and activated point mutants / peptidyl-serine phosphorylation / protein phosphatase binding / angiogenesis / protein autophosphorylation / negative regulation of translation / 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 / identical protein binding / membrane / 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. / Protein kinase domain / WD40/YVTN repeat-like-containing domain superfamily ...: / 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. / Protein kinase domain / WD40/YVTN repeat-like-containing domain superfamily / 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-3Z3 / 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: 1.8 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, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Source and taxonomy / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / entity_src_gen / pdbx_initial_refinement_model / pdbx_struct_assembly / pdbx_struct_assembly_prop / pdbx_struct_oper_list / struct_keywords
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)37,6174
Polymers36,8161
Non-polymers8013
Water4,720262
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area510 Å2
ΔGint-1 kcal/mol
Surface area13900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.757, 81.757, 128.621
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-1231-

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-3Z3 / 4-{2-amino-3-[5-fluoro-2-(methylamino)quinazolin-6-yl]-4-methylbenzoyl}-1-methyl-2,5-diphenyl-1,2-dihydro-3H-pyrazol-3-one


Mass: 558.605 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H27FN6O2
#3: Chemical ChemComp-TLA / L(+)-TARTARIC ACID


Mass: 150.087 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H6O6
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 262 / 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: 2.92 Å3/Da / Density % sol: 57.86 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 0.18M Na/K Tartrate, 5% PEG-3350, 0.1M HEPES pH 7.0

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Data collection

DiffractionMean temperature: 80 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.9774 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jun 6, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9774 Å / Relative weight: 1
ReflectionResolution: 1.8→50 Å / Num. obs: 41166 / % possible obs: 100 % / Redundancy: 10.4 % / Rmerge(I) obs: 0.102 / Χ2: 1.112 / Net I/av σ(I): 26.78 / Net I/σ(I): 8.3 / Num. measured all: 426553
Reflection shell

Diffraction-ID: 1 / Rejects: _ / % possible all: 100

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2
1.8-1.8610.50.95440530.727
1.86-1.9410.50.68240230.783
1.94-2.0310.50.43940510.841
2.03-2.1310.50.29240490.932
2.13-2.2710.50.20940821.08
2.27-2.4410.50.15440501.113
2.44-2.6910.40.11841161.073
2.69-3.0810.40.09941221.209
3.08-3.8810.20.10141971.84
3.88-509.70.0644231.515

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Processing

Software
NameVersionClassification
HKL-2000data reduction
REFMAC5.5.0109refinement
PDB_EXTRACT3.15data extraction
HKL-2000data scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4X7J

4x7j


Resolution: 1.8→40.88 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.959 / SU B: 3.976 / SU ML: 0.059 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.094 / ESU R Free: 0.091 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.1957 2082 5.1 %RANDOM
Rwork0.1762 38762 --
obs0.1771 41048 99.5 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 68.41 Å2 / Biso mean: 30.17 Å2 / Biso min: 9.99 Å2
Baniso -1Baniso -2Baniso -3
1-0.37 Å20 Å20 Å2
2--0.37 Å20 Å2
3----0.74 Å2
Refinement stepCycle: final / Resolution: 1.8→40.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2121 0 58 262 2441
Biso mean--24.84 29.64 -
Num. residues----260
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0222261
X-RAY DIFFRACTIONr_angle_refined_deg1.0571.9993065
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.7185267
X-RAY DIFFRACTIONr_dihedral_angle_2_deg28.81623.551107
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.4215398
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.5991517
X-RAY DIFFRACTIONr_chiral_restr0.070.2328
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0211728
X-RAY DIFFRACTIONr_mcbond_it0.8221.51315
X-RAY DIFFRACTIONr_mcangle_it1.49122140
X-RAY DIFFRACTIONr_scbond_it2.3623946
X-RAY DIFFRACTIONr_scangle_it3.6934.5920
LS refinement shellResolution: 1.801→1.848 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.298 161 -
Rwork0.286 2757 -
all-2918 -
obs--98.55 %
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)
11.9176-0.22990.16251.5715-0.8943.73210.1019-0.0472-0.2639-0.10810.00530.07060.3878-0.1153-0.10720.0457-0.0185-0.02740.02570.01930.053419.66956.69313.3167
22.2566-0.2415-0.55531.2428-0.04443.69140.0339-0.17290.01560.0445-0.037-0.17390.01010.29270.00310.0108-0.0113-0.01020.04170.01240.033245.076715.4096.6765
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A585 - 889
2X-RAY DIFFRACTION2A890 - 1085

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