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- PDB-4x7n: Co-crystal Structure of PERK bound to 4-[2-amino-4-methyl-3-(2-me... -

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Basic information

Entry
Database: PDB / ID: 4x7n
TitleCo-crystal Structure of PERK bound to 4-[2-amino-4-methyl-3-(2-methylquinolin-6-yl)benzoyl]-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 / 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-3Z5 / L(+)-TARTARIC ACID / Eukaryotic translation initiation factor 2-alpha kinase 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.35 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)37,4913
Polymers36,8161
Non-polymers6752
Water1,31573
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area220 Å2
ΔGint0 kcal/mol
Surface area13930 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.576, 81.576, 128.840
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-1216-

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-3Z5 / 4-[2-amino-4-methyl-3-(2-methylquinolin-6-yl)benzoyl]-1-methyl-2,5-diphenyl-1,2-dihydro-3H-pyrazol-3-one


Mass: 524.612 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H28N4O2
#3: Chemical ChemComp-TLA / L(+)-TARTARIC ACID / Tartaric acid


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


Mass: 18.015 Da / Num. of mol.: 73 / 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: 2.91 Å3/Da / Density % sol: 57.75 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: 0.4M Na/K Tartrate, 0.1M HEPES pH 7.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.54178 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Jul 13, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 2.35→50 Å / Num. obs: 18581 / % possible obs: 98.6 % / Redundancy: 4.7 % / Rmerge(I) obs: 0.13 / Χ2: 1.037 / Net I/av σ(I): 11.94 / Net I/σ(I): 5.9 / Num. measured all: 87641
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2.35-2.433.80.60417060.88692.7
2.43-2.534.80.54318370.949100
2.53-2.654.80.45618300.879100
2.65-2.794.80.36118480.908100
2.79-2.964.80.29118480.96999.8
2.96-3.194.80.1981868199.8
3.19-3.514.80.12518651.07599.6
3.51-4.024.90.08418821.18799.3
4.02-5.064.80.06319131.21998.8
5.06-504.60.05819841.23296.3

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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: 2.35→40.79 Å / Cor.coef. Fo:Fc: 0.93 / Cor.coef. Fo:Fc free: 0.91 / SU B: 13.005 / SU ML: 0.147 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.26 / ESU R Free: 0.212 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2454 961 5.2 %RANDOM
Rwork0.2092 17462 --
obs0.211 -98.08 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 68.58 Å2 / Biso mean: 28.947 Å2 / Biso min: 2 Å2
Baniso -1Baniso -2Baniso -3
1-0.29 Å20 Å20 Å2
2--0.29 Å20 Å2
3----0.58 Å2
Refinement stepCycle: final / Resolution: 2.35→40.79 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2122 0 50 73 2245
Biso mean--22.1 16.78 -
Num. residues----259
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0222236
X-RAY DIFFRACTIONr_angle_refined_deg1.0621.9943026
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.6675260
X-RAY DIFFRACTIONr_dihedral_angle_2_deg28.94923.551107
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.39315397
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.511517
X-RAY DIFFRACTIONr_chiral_restr0.0690.2324
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0211707
X-RAY DIFFRACTIONr_mcbond_it0.3281.51300
X-RAY DIFFRACTIONr_mcangle_it0.63822115
X-RAY DIFFRACTIONr_scbond_it0.9483936
X-RAY DIFFRACTIONr_scangle_it1.5754.5909
LS refinement shellResolution: 2.35→2.411 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.315 64 -
Rwork0.27 1174 -
all-1238 -
obs--91.3 %
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)
11.1594-0.1270.0961.3718-0.75444.44070.1035-0.0349-0.3193-0.15210.00930.08920.5244-0.2567-0.11270.073-0.0344-0.04490.07160.00170.117319.58296.53683.2411
22.327-0.2857-0.63381.3108-0.20334.59130.0704-0.1377-0.01980.0182-0.0739-0.1821-0.00980.35380.00350.0071-0.009-0.00410.04510.00410.050744.98915.26276.5052
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A585 - 889
2X-RAY DIFFRACTION2A890 - 1085

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