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- PDB-4g34: Crystal Structure of GSK6924 Bound to PERK (R587-R1092, delete A6... -

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Basic information

Entry
Database: PDB / ID: 4g34
TitleCrystal Structure of GSK6924 Bound to PERK (R587-R1092, delete A660-T867) at 2.70 A Resolution
ComponentsEukaryotic translation initiation factor 2-alpha kinase 3
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / deletion mutant / catalytic domain / synthetic inhibitor / 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-924 / Eukaryotic translation initiation factor 2-alpha kinase 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsGampe, R.T. / Axten, J.M.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Discovery of 7-Methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a Potent and Selective First-in-Class Inhibitor of ...Title: Discovery of 7-Methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a Potent and Selective First-in-Class Inhibitor of Protein Kinase R (PKR)-like Endoplasmic Reticulum Kinase (PERK).
Authors: Axten, J.M. / Medina, J.R. / Feng, Y. / Shu, A. / Romeril, S.P. / Grant, S.W. / Li, W.H. / Heerding, D.A. / Minthorn, E. / Mencken, T. / Atkins, C. / Liu, Q. / Rabindran, S. / Kumar, R. / ...Authors: Axten, J.M. / Medina, J.R. / Feng, Y. / Shu, A. / Romeril, S.P. / Grant, S.W. / Li, W.H. / Heerding, D.A. / Minthorn, E. / Mencken, T. / Atkins, C. / Liu, Q. / Rabindran, S. / Kumar, R. / Hong, X. / Goetz, A. / Stanley, T. / Taylor, J.D. / Sigethy, S.D. / Tomberlin, G.H. / Hassell, A.M. / Kahler, K.M. / Shewchuk, L.M. / Gampe, R.T.
History
DepositionJul 13, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 8, 2012Provider: repository / Type: Initial release
Revision 1.1Sep 5, 2012Group: Database references
Revision 1.2Jul 26, 2017Group: Refinement description / Source and taxonomy / Category: entity_src_gen / software
Revision 1.3Sep 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)35,1832
Polymers34,7971
Non-polymers3851
Water93752
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)101.460, 101.460, 158.312
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122

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Components

#1: Protein Eukaryotic translation initiation factor 2-alpha kinase 3 / PKR-like endoplasmic reticulum kinase / PERK / Pancreatic eIF2-alpha kinase / HsPEK


Mass: 34797.215 Da / Num. of mol.: 1 / Fragment: UNP residues 588-660,869-1093
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-924 / 1-[5-(4-aminothieno[3,2-c]pyridin-3-yl)-2,3-dihydro-1H-indol-1-yl]-2-phenylethanone


Mass: 385.481 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H19N3OS
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 52 / 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: 3.38 Å3/Da / Density % sol: 63.61 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 100 mM BTP, pH 7.0, 3.5 - 4.9 M linear gradient of ammonium acetate, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.97872 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Mar 5, 2010
RadiationMonochromator: diamond(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 2.7→45.239 Å / Num. all: 13940 / Num. obs: 13061 / % possible obs: 100 % / Redundancy: 20.8 % / Biso Wilson estimate: 39 Å2 / Rmerge(I) obs: 0.092 / Net I/σ(I): 32.5
Reflection shellResolution: 2.7→2.8 Å / Redundancy: 19.4 % / Rmerge(I) obs: 0.584 / Mean I/σ(I) obs: 5.67 / Num. unique all: 1354 / % possible all: 100

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Processing

Software
NameVersionClassification
MD2MAR LSCatdata collection
MOLREPphasing
REFMAC5.5.0109refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2A19

2a19


Resolution: 2.7→45.239 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.901 / SU B: 19.543 / SU ML: 0.193 / Cross valid method: THROUGHOUT / ESU R: 0.385 / ESU R Free: 0.285 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : RESIDUAL ONLY
RfactorNum. reflection% reflectionSelection details
Rfree0.25762 688 5 %RANDOM
Rwork0.20818 ---
obs0.21049 13061 99.28 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 66.856 Å2
Baniso -1Baniso -2Baniso -3
1-1.76 Å20.88 Å20 Å2
2--1.76 Å20 Å2
3----2.63 Å2
Refinement stepCycle: LAST / Resolution: 2.7→45.239 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1997 0 28 52 2077
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0222100
X-RAY DIFFRACTIONr_angle_refined_deg1.1251.9842841
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.6835251
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.34523.93999
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.07415371
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.8921514
X-RAY DIFFRACTIONr_chiral_restr0.0720.2305
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0211645
X-RAY DIFFRACTIONr_mcbond_it0.3181.51254
X-RAY DIFFRACTIONr_mcangle_it0.62622029
X-RAY DIFFRACTIONr_scbond_it0.9563846
X-RAY DIFFRACTIONr_scangle_it1.6644.5812
LS refinement shellResolution: 2.7→2.77 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.28 54 -
Rwork0.275 932 -
obs--98.7 %
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)
15.460.58312.05873.72711.0365.6943-0.0794-0.015-0.50680.16620.2233-0.66780.5040.943-0.14380.27240.09450.00840.3299-0.07520.208555.232-9.2212.383
21.28051.08920.55725.5657-1.55814.48910.14-0.28380.00260.30270.14140.1967-0.0833-0.4653-0.28130.11050.09840.01030.3160.04880.028632.474-23.0995.101
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A586 - 892
2X-RAY DIFFRACTION2A893 - 1078

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