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- PDB-8eqe: Co-crystal structure of PERK with compound 26 -

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Basic information

Entry
Database: PDB / ID: 8eqe
TitleCo-crystal structure of PERK with compound 26
ComponentsEukaryotic translation initiation factor 2-alpha kinase 3
KeywordsTRANSFERASE / kinase / PERK / inhibitor
Function / homology
Function and homology information


regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / 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 ...regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / 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 / Modulation of host responses by IFN-stimulated genes / regulation of translational initiation / ER overload response / cellular response to cold / 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 / ossification / insulin-like growth factor receptor signaling pathway / cellular response to amino acid starvation / response to endoplasmic reticulum stress / eukaryotic translation initiation factor 2alpha kinase activity / 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 tyrosine kinase activity / angiogenesis / protein phosphatase binding / non-specific serine/threonine protein kinase / protein kinase activity / negative regulation of translation / 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 / nucleus / membrane / cytosol / cytoplasm
Similarity search - Function
: / Quinoprotein alcohol dehydrogenase-like superfamily / 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. ...: / Quinoprotein alcohol dehydrogenase-like superfamily / 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
Similarity search - Domain/homology
Chem-WQ2 / Eukaryotic translation initiation factor 2-alpha kinase 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.559 Å
AuthorsZhu, G. / Surman, M.D. / Mulvihill, M.J.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: Pharmaceutics / Year: 2022
Title: Optimization of a Novel Mandelamide-Derived Pyrrolopyrimidine Series of PERK Inhibitors.
Authors: Stokes, M.E. / Surman, M.D. / Calvo, V. / Surguladze, D. / Li, A.H. / Gasparek, J. / Betzenhauser, M. / Zhu, G. / Du, H. / Rigby, A.C. / Mulvihill, M.J.
History
DepositionOct 7, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 30, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 25, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / pdbx_initial_refinement_model
Item: _citation.country

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
AAA: Eukaryotic translation initiation factor 2-alpha kinase 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,2862
Polymers36,8161
Non-polymers4691
Water1086
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)125.342, 125.342, 58.084
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221

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Components

#1: Protein 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
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-WQ2 / (2R)-N-[(4M)-4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl]-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide


Mass: 469.459 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H22F3N5O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 6 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 3.58 Å3/Da / Density % sol: 65.62 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 4% tacsimate pH 7.0 and 12% PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1.0332 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 17, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 2.559→54.275 Å / Num. obs: 17214 / % possible obs: 100 % / Redundancy: 9.7 % / Rmerge(I) obs: 0.072 / Net I/σ(I): 15
Reflection shellResolution: 2.559→2.63 Å / Rmerge(I) obs: 1.18 / Num. unique obs: 1254

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
DIALSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4X7J

4x7j


Resolution: 2.559→54.275 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.923 / SU B: 19.599 / SU ML: 0.338 / Cross valid method: FREE R-VALUE / ESU R: 0.308 / ESU R Free: 0.272
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2873 883 5.135 %
Rwork0.2242 16312 -
all0.227 --
obs-17195 99.866 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 78.053 Å2
Baniso -1Baniso -2Baniso -3
1--4.949 Å2-2.474 Å2-0 Å2
2---4.949 Å20 Å2
3---16.055 Å2
Refinement stepCycle: LAST / Resolution: 2.559→54.275 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2108 0 34 6 2148
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0030.0132193
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172071
X-RAY DIFFRACTIONr_angle_refined_deg1.2491.6742963
X-RAY DIFFRACTIONr_angle_other_deg1.0551.5874796
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4115252
X-RAY DIFFRACTIONr_dihedral_angle_2_deg29.00721.57121
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.92515397
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.0161517
X-RAY DIFFRACTIONr_chiral_restr0.0430.2272
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.022383
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02482
X-RAY DIFFRACTIONr_nbd_refined0.1930.2431
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1690.21916
X-RAY DIFFRACTIONr_nbtor_refined0.1650.21035
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0720.21067
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1340.240
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.0970.24
X-RAY DIFFRACTIONr_nbd_other0.1620.235
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1930.25
X-RAY DIFFRACTIONr_mcbond_it3.8938.2261020
X-RAY DIFFRACTIONr_mcbond_other3.8918.2221021
X-RAY DIFFRACTIONr_mcangle_it6.52612.31269
X-RAY DIFFRACTIONr_mcangle_other6.52712.3111269
X-RAY DIFFRACTIONr_scbond_it3.1328.4891173
X-RAY DIFFRACTIONr_scbond_other3.1318.4871174
X-RAY DIFFRACTIONr_scangle_it5.5212.6061694
X-RAY DIFFRACTIONr_scangle_other5.51812.6041695
X-RAY DIFFRACTIONr_lrange_it8.77291.362411
X-RAY DIFFRACTIONr_lrange_other8.7791.342412
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
2.559-2.6250.48760.47711600.47712520.0190.02498.7220.446
2.625-2.6970.42580.43311490.43212070.1190.0871000.407
2.697-2.7750.502740.41211440.41712200.1550.20199.83610.377
2.775-2.860.38670.39810740.39711420.4670.5199.91240.357
2.86-2.9540.378580.3410760.34211340.6140.6721000.308
2.954-3.0570.466590.33110260.33910850.6620.7011000.301
3.057-3.1720.422560.3089870.31410430.710.7471000.281
3.172-3.3010.406470.2839720.2910190.7040.7931000.258
3.301-3.4470.323460.2519220.2539680.7780.871000.233
3.447-3.6150.287600.2588840.2619440.8950.891000.248
3.615-3.8090.22350.2168330.2168680.9210.921000.21
3.809-4.0390.277560.2117930.2158510.9270.93599.7650.206
4.039-4.3170.201410.1787530.187940.9380.9461000.179
4.317-4.660.204320.1626990.1647310.9520.9631000.17
4.66-5.1010.178230.1526620.1536850.9610.9661000.16
5.101-5.6970.231170.1756140.1776310.9510.9551000.181
5.697-6.5660.299300.1915230.1965530.9130.9441000.202
6.566-8.0120.359190.1574560.1634750.8990.9621000.171
8.012-11.210.139230.1373600.1383830.9760.9741000.16
11.21-54.2750.34360.2232250.2262310.8180.9451000.246

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