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- PDB-7mf0: Co-crystal structure of PERK with inhibitor (R)-2-amino-N-cyclopr... -

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Basic information

Entry
Database: PDB / ID: 7mf0
TitleCo-crystal structure of PERK with inhibitor (R)-2-amino-N-cyclopropyl-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-methylphenyl)nicotinamide
ComponentsEukaryotic translation initiation factor 2-alpha kinase 3,Eukaryotic translation initiation factor 2-alpha kinase 3
KeywordsTRANSFERASE / Kinase / PERK / inhibitor / HC5469
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 / 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 / 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 / positive regulation of gene expression / endoplasmic reticulum membrane / perinuclear region of cytoplasm / enzyme binding / endoplasmic reticulum / ATP binding / identical protein binding / membrane / nucleus / cytoplasm / cytosol
Similarity search - Function
Quinoprotein alcohol dehydrogenase-like superfamily / 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
Similarity search - Domain/homology
Chem-Z6P / Eukaryotic translation initiation factor 2-alpha kinase 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.809 Å
AuthorsWiens, B. / Koszelak-Rosenblum, M. / Surman, M.D. / Zhu, G. / Mulvihill, M.J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2021
Title: Discovery of 2-amino-3-amido-5-aryl-pyridines as highly potent, orally bioavailable, and efficacious PERK kinase inhibitors.
Authors: Calvo, V. / Surguladze, D. / Li, A.H. / Surman, M.D. / Malibhatla, S. / Bandaru, M. / Jonnalagadda, S.K. / Adarasandi, R. / Velmala, M. / Singireddi, D.R.P. / Velpuri, M. / Nareddy, B.R. / ...Authors: Calvo, V. / Surguladze, D. / Li, A.H. / Surman, M.D. / Malibhatla, S. / Bandaru, M. / Jonnalagadda, S.K. / Adarasandi, R. / Velmala, M. / Singireddi, D.R.P. / Velpuri, M. / Nareddy, B.R. / Sastry, V. / Mandati, C. / Guguloth, R. / Siddiqui, S. / Patil, B.S. / Chad, E. / Wolfley, J. / Gasparek, J. / Feldman, K. / Betzenhauser, M. / Wiens, B. / Koszelak-Rosenblum, M. / Zhu, G. / Du, H. / Rigby, A.C. / Mulvihill, M.J.
History
DepositionApr 8, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 19, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: atom_type / chem_comp_atom ...atom_type / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z ..._atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z / _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
AAA: 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)37,2692
Polymers36,8161
Non-polymers4521
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)73.827, 84.958, 70.031
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212

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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
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-Z6P / 2-amino-N-cyclopropyl-5-(4-{[(2R)-2-(3,5-difluorophenyl)-2-hydroxyacetyl]amino}-2-methylphenyl)pyridine-3-carboxamide


Mass: 452.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H22F2N4O3 / 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: 2.98 Å3/Da / Density % sol: 58.76 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 5.6
Details: 15% MPD, 10% PEG 8K, 0.1M MgCl2, 0.1M sodium citrate pH 5.6

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1.033 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: 1.033 Å / Relative weight: 1
ReflectionResolution: 2.809→56 Å / Num. obs: 11251 / % possible obs: 100 % / Redundancy: 6.3 % / Rmerge(I) obs: 0.118 / Rpim(I) all: 0.053 / Rrim(I) all: 0.131 / Net I/σ(I): 6.5
Reflection shellResolution: 2.809→2.88 Å / Rmerge(I) obs: 0.865 / Mean I/σ(I) obs: 1.7 / Num. unique obs: 819 / Rpim(I) all: 0.35 / Rrim(I) all: 0.901

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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: 2.809→55.726 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.914 / SU B: 22.176 / SU ML: 0.385 / Cross valid method: FREE R-VALUE / ESU R: 0.678 / ESU R Free: 0.35
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2725 540 4.813 %
Rwork0.232 10679 -
all0.234 --
obs-11219 99.884 %
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: 90.189 Å2
Baniso -1Baniso -2Baniso -3
1--14.449 Å2-0 Å2-0 Å2
2--2.416 Å2-0 Å2
3---12.033 Å2
Refinement stepCycle: LAST / Resolution: 2.809→55.726 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2122 0 33 0 2155
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0030.0132206
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172126
X-RAY DIFFRACTIONr_angle_refined_deg1.2651.6712979
X-RAY DIFFRACTIONr_angle_other_deg1.1171.5894898
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7515256
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.20721.653121
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.51915401
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.3771517
X-RAY DIFFRACTIONr_chiral_restr0.0440.2274
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.022427
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02515
X-RAY DIFFRACTIONr_nbd_refined0.1910.2456
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1680.22002
X-RAY DIFFRACTIONr_nbtor_refined0.1640.21022
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0730.21147
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1330.245
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1990.26
X-RAY DIFFRACTIONr_nbd_other0.1390.230
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1620.23
X-RAY DIFFRACTIONr_mcbond_it4.2639.4621033
X-RAY DIFFRACTIONr_mcbond_other4.2619.4611034
X-RAY DIFFRACTIONr_mcangle_it7.04614.1651287
X-RAY DIFFRACTIONr_mcangle_other7.04614.1711287
X-RAY DIFFRACTIONr_scbond_it3.5679.6611172
X-RAY DIFFRACTIONr_scbond_other3.5689.6631171
X-RAY DIFFRACTIONr_scangle_it6.13714.3981689
X-RAY DIFFRACTIONr_scangle_other6.13614.3961690
X-RAY DIFFRACTIONr_lrange_it9.698106.0312430
X-RAY DIFFRACTIONr_lrange_other9.696106.0092431
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
2.809-2.8820.402410.4037690.4038120.3450.3599.75370.385
2.882-2.9610.385400.3747440.3757850.6010.49499.87260.361
2.961-3.0470.275450.3477430.3427890.690.61399.87330.335
3.047-3.140.309360.3047000.3057360.7530.6821000.296
3.14-3.2430.355320.3056860.3067180.6820.7331000.291
3.243-3.3560.308340.2836830.2847170.7730.8031000.271
3.356-3.4820.255280.2416420.2426710.8570.87799.8510.239
3.482-3.6240.29320.2336230.2356570.8540.89399.69560.221
3.624-3.7840.246260.2186040.2196300.8760.9141000.215
3.784-3.9680.2310.2035670.2035980.9210.9281000.199
3.968-4.1820.255360.2015510.2045870.8930.9341000.202
4.182-4.4340.24210.1985330.25540.9250.9381000.207
4.434-4.7380.275300.1784910.1835210.9250.9541000.193
4.738-5.1140.124220.1724630.1694850.970.9631000.185
5.114-5.5980.23390.1984350.1984440.9340.9471000.208
5.598-6.2510.235190.2413930.2414130.9230.91599.75790.256
6.251-7.2020.34200.1993480.2073690.8950.93999.7290.217
7.202-8.7840.2130.1813090.1823230.9450.95699.69040.2
8.784-12.2720.2130.1742440.1762580.9390.96299.61240.2
12.272-55.7260.492120.3581500.3681630.8150.85699.38650.505

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