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- PDB-4m7i: Crystal Structure of GSK6157 Bound to PERK (R587-R1092, delete A6... -

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Basic information

Entry
Database: PDB / ID: 4m7i
TitleCrystal Structure of GSK6157 Bound to PERK (R587-R1092, delete A660-T867) at 2.34A Resolution
ComponentsEukaryotic translation initiation factor 2-alpha kinase 3
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / deletion mutant / catalytic domain / 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 / ER overload response / positive regulation of transcription by RNA polymerase I / 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 / Signaling by ALK fusions and activated point mutants / positive regulation of protein localization to nucleus / activation of cysteine-type endopeptidase activity involved in apoptotic process / KEAP1-NFE2L2 pathway / 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 / 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-27D / Eukaryotic translation initiation factor 2-alpha kinase 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Difference density / Resolution: 2.34 Å
AuthorsGampe, R.T. / Axten, J.M.
CitationJournal: To be Published
Title: Discovery of 5-{4-fluoro-1-[(6-methyl-2-pyridinyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2656157), a Potent and Selective PERK Inhibitor Selected ...Title: Discovery of 5-{4-fluoro-1-[(6-methyl-2-pyridinyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2656157), a Potent and Selective PERK Inhibitor Selected for Preclinical Development
Authors: Axten, J.M. / Romeril, S.P. / Shu, A. / Ralph, J. / Medina, J.R. / Feng, Y. / Li, W.H.H. / Grant, S.W. / Heerding, D.A. / Minthorn, E. / Mencken, T. / Gaul, N. / Goetz, A. / Stanley, T. / ...Authors: Axten, J.M. / Romeril, S.P. / Shu, A. / Ralph, J. / Medina, J.R. / Feng, Y. / Li, W.H.H. / Grant, S.W. / Heerding, D.A. / Minthorn, E. / Mencken, T. / Gaul, N. / Goetz, A. / Stanley, T. / Hassell, A.M. / Gampe, R.T. / Atkins, C. / Kumar, R.
History
DepositionAug 12, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 3, 2014Provider: repository / Type: Initial release
Revision 1.1Aug 23, 2017Group: Source and taxonomy / Category: entity_src_gen
Revision 1.2Nov 15, 2017Group: Refinement description / Category: software
Revision 1.3Sep 20, 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)35,2122
Polymers34,7971
Non-polymers4141
Water2,234124
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)101.060, 101.060, 158.028
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-27D / 1-[5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluoro-1H-indol-1-yl]-2-(6-methylpyridin-2-yl)ethanone


Mass: 414.435 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H19FN6O
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 124 / 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: 3.35 Å3/Da / Density % sol: 63.25 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 100 mM BTP at pH 7.0 with a 3.5 4.9M 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 MX300HS / Detector: CCD / Date: Oct 20, 2010
RadiationMonochromator: C(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 2.34→48 Å / Num. all: 20797 / Num. obs: 20779 / % possible obs: 99.9 % / Observed criterion σ(I): -3 / Redundancy: 11.8 % / Rmerge(I) obs: 0.05 / Net I/σ(I): 44.5
Reflection shellResolution: 2.34→2.42 Å / Redundancy: 12 % / Rmerge(I) obs: 0.408 / Mean I/σ(I) obs: 6.9 / Num. unique all: 2032 / % possible all: 100

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Processing

Software
NameVersionClassification
MD2Mar LSCatdata collection
PHENIX(phenix.refine: dev_551)refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: Difference density
Starting model: PDB entry 4G31

4g31


Resolution: 2.34→29.324 Å / SU ML: 0.35 / σ(F): 1.33 / Phase error: 27.15 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2816 673 3.25 %
Rwork0.2074 --
obs0.2095 20731 99.75 %
all-20797 -
Solvent computationShrinkage radii: 0.83 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 60 Å2 / ksol: 0.321 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-12.0528 Å20 Å2-0 Å2
2--12.0528 Å2-0 Å2
3----17.554 Å2
Refinement stepCycle: LAST / Resolution: 2.34→29.324 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1974 0 31 124 2129
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072056
X-RAY DIFFRACTIONf_angle_d1.0122779
X-RAY DIFFRACTIONf_dihedral_angle_d14.488764
X-RAY DIFFRACTIONf_chiral_restr0.065301
X-RAY DIFFRACTIONf_plane_restr0.004353
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.34-2.52060.35561370.27753900X-RAY DIFFRACTION100
2.5206-2.77410.33961400.26173923X-RAY DIFFRACTION100
2.7741-3.17510.35491320.22973971X-RAY DIFFRACTION100
3.1751-3.99870.26441320.19674016X-RAY DIFFRACTION100
3.9987-29.3240.24771320.19044248X-RAY DIFFRACTION100

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