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- PDB-8eqd: Co-crystal structure of PERK with compound 24 -

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Basic information

Entry
Database: PDB / ID: 8eqd
TitleCo-crystal structure of PERK with compound 24
ComponentsEukaryotic translation initiation factor 2-alpha kinase 3
KeywordsTRANSFERASE / kinase / PERK / inhibitor
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 / 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-WPX / Eukaryotic translation initiation factor 2-alpha kinase 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.92 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

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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)37,2362
Polymers36,8161
Non-polymers4191
Water00
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)125.900, 125.900, 55.216
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-WPX / (2R)-N-[(4M)-4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylphenyl]-2-(3-fluorophenyl)-2-hydroxyacetamide


Mass: 419.451 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H22FN5O2 / Feature type: SUBJECT OF INVESTIGATION
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: 3.43 Å3/Da / Density % sol: 64.15 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 100 mM HEPES pH 7.0, 180 mM Na/K tartrate, 9% PEG3350

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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: Jun 11, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 2.92→41.51 Å / Num. obs: 10640 / % possible obs: 95.3 % / Redundancy: 6.7 % / CC1/2: 0.997 / Rmerge(I) obs: 0.097 / Net I/σ(I): 9.5
Reflection shellResolution: 2.92→2.97 Å / Rmerge(I) obs: 0.794 / Num. unique obs: 510 / CC1/2: 0.817

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
DIALSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4X7J

4x7j


Resolution: 2.92→41.51 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.938 / SU B: 42.134 / SU ML: 0.584 / Cross valid method: FREE R-VALUE / ESU R: 0.865 / ESU R Free: 0.388
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2796 509 4.788 %
Rwork0.246 10122 -
all0.248 --
obs-10631 95.149 %
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: 93.984 Å2
Baniso -1Baniso -2Baniso -3
1--8.076 Å2-4.038 Å2-0 Å2
2---8.076 Å20 Å2
3---26.199 Å2
Refinement stepCycle: LAST / Resolution: 2.92→41.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2106 0 31 0 2137
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0020.0132187
X-RAY DIFFRACTIONr_bond_other_d0.0010.0152110
X-RAY DIFFRACTIONr_angle_refined_deg1.211.672953
X-RAY DIFFRACTIONr_angle_other_deg0.9791.5914851
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7715252
X-RAY DIFFRACTIONr_dihedral_angle_2_deg27.15721.57121
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.41415397
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.1931517
X-RAY DIFFRACTIONr_chiral_restr0.0350.2271
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.022406
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02522
X-RAY DIFFRACTIONr_nbd_refined0.1830.2463
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1610.22069
X-RAY DIFFRACTIONr_nbtor_refined0.160.21027
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0720.21075
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1440.251
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2090.26
X-RAY DIFFRACTIONr_nbd_other0.1840.233
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1760.24
X-RAY DIFFRACTIONr_mcbond_it3.0939.9521020
X-RAY DIFFRACTIONr_mcbond_other3.0829.9481019
X-RAY DIFFRACTIONr_mcangle_it5.49914.8991268
X-RAY DIFFRACTIONr_mcangle_other5.49714.8951269
X-RAY DIFFRACTIONr_scbond_it2.12810.091167
X-RAY DIFFRACTIONr_scbond_other2.12710.0881168
X-RAY DIFFRACTIONr_scangle_it4.0615.051685
X-RAY DIFFRACTIONr_scangle_other4.05915.0471686
X-RAY DIFFRACTIONr_lrange_it8.277112.9732458
X-RAY DIFFRACTIONr_lrange_other8.275112.9472459
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
2.92-2.9950.428410.4817240.4787910.1050.09596.7130.437
2.995-3.0770.582380.4487340.4548120.0510.06395.07390.404
3.077-3.1660.439420.4246940.4257550.0530.06997.48340.376
3.166-3.2620.422360.4066810.4077570.0870.07894.7160.357
3.262-3.3690.388250.46680.3997020.1740.17298.71790.359
3.369-3.4860.356280.3586590.3587230.3470.32495.02070.323
3.486-3.6170.346300.3316250.3326730.4890.45997.32540.299
3.617-3.7630.52200.2825930.2866450.4560.64895.03880.26
3.763-3.9290.392390.2665800.2736540.7570.77694.64830.254
3.929-4.1190.259300.2385280.245810.8650.84196.04130.222
4.119-4.3390.239310.2035230.2055860.9070.90794.53920.188
4.339-4.60.225210.1765000.1785570.9440.94393.53680.165
4.6-4.9130.16170.1554730.1555080.9580.95796.45670.147
4.913-5.30.134230.1594350.1584820.970.96295.02070.153
5.3-5.7970.244260.1753880.1794420.9080.9593.66520.166
5.797-6.4650.249180.23610.2024100.9180.93192.4390.192
6.465-7.4350.237110.1783270.183620.9430.93893.37020.172
7.435-9.0340.162160.1672760.1673190.9490.9591.5360.168
9.034-12.4840.27130.1572140.1642480.9650.96791.53230.16
12.484-41.510.24240.2771380.2751600.990.90888.750.295

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