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- PDB-4qte: Structure of ERK2 in complex with VTX-11e, 4-{2-[(2-CHLORO-4-FLUO... -

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Basic information

Entry
Database: PDB / ID: 4qte
TitleStructure of ERK2 in complex with VTX-11e, 4-{2-[(2-CHLORO-4-FLUOROPHENYL)AMINO]-5-METHYLPYRIMIDIN-4-YL}-N-[(1S)-1-(3-CHLOROPHENYL)-2-HYDROXYETHYL]-1H-PYRROLE-2-CARBOXAMIDE
ComponentsMitogen-activated protein kinase 1
KeywordsTransferase/transferase inhibitor / Structural Genomics / Structural Genomics Consortium / SGC / TRANSFERASE / kinase / MAPK / signalling / inhibitor / allosteric / Structural Genomics Consortium (SGC) / Transferase-transferase inhibitor complex
Function / homology
Function and homology information


phospho-PLA2 pathway / Signaling by MAPK mutants / RAF-independent MAPK1/3 activation / Suppression of apoptosis / Signaling by Activin / Gastrin-CREB signalling pathway via PKC and MAPK / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / cytosine metabolic process / ERKs are inactivated ...phospho-PLA2 pathway / Signaling by MAPK mutants / RAF-independent MAPK1/3 activation / Suppression of apoptosis / Signaling by Activin / Gastrin-CREB signalling pathway via PKC and MAPK / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / cytosine metabolic process / ERKs are inactivated / response to epidermal growth factor / Signaling by MAP2K mutants / Signaling by NODAL / RSK activation / Golgi Cisternae Pericentriolar Stack Reorganization / regulation of cellular pH / positive regulation of macrophage proliferation / outer ear morphogenesis / Regulation of the apoptosome activity / regulation of Golgi inheritance / ERBB signaling pathway / labyrinthine layer blood vessel development / mammary gland epithelial cell proliferation / trachea formation / Negative feedback regulation of MAPK pathway / regulation of early endosome to late endosome transport / regulation of stress-activated MAPK cascade / IFNG signaling activates MAPKs / Frs2-mediated activation / positive regulation of macrophage chemotaxis / lung morphogenesis / ERBB2-ERBB3 signaling pathway / response to exogenous dsRNA / regulation of cytoskeleton organization / Activation of the AP-1 family of transcription factors / face development / ERK/MAPK targets / androgen receptor signaling pathway / pseudopodium / RUNX2 regulates osteoblast differentiation / Recycling pathway of L1 / progesterone receptor signaling pathway / MAPK1 (ERK2) activation / negative regulation of cell differentiation / Bergmann glial cell differentiation / positive regulation of telomere capping / thyroid gland development / Advanced glycosylation endproduct receptor signaling / steroid hormone mediated signaling pathway / RHO GTPases Activate NADPH Oxidases / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / Regulation of HSF1-mediated heat shock response / MAP kinase activity / regulation of ossification / RHO GTPases Activate WASPs and WAVEs / Nuclear events stimulated by ALK signaling in cancer / mitogen-activated protein kinase / phosphatase binding / Signal attenuation / Estrogen-stimulated signaling through PRKCZ / Schwann cell development / stress-activated MAPK cascade / Growth hormone receptor signaling / lipopolysaccharide-mediated signaling pathway / positive regulation of telomerase activity / cellular response to cadmium ion / cellular response to amino acid starvation / positive regulation of telomere maintenance via telomerase / ERK1 and ERK2 cascade / NPAS4 regulates expression of target genes / myelination / NCAM signaling for neurite out-growth / phosphotyrosine residue binding / RNA polymerase II CTD heptapeptide repeat kinase activity / ESR-mediated signaling / insulin-like growth factor receptor signaling pathway / thymus development / positive regulation of peptidyl-threonine phosphorylation / Regulation of PTEN gene transcription / Signal transduction by L1 / caveola / long-term synaptic potentiation / Negative regulation of FGFR3 signaling / Downregulation of SMAD2/3:SMAD4 transcriptional activity / FCERI mediated MAPK activation / Negative regulation of FGFR2 signaling / FCGR3A-mediated phagocytosis / Negative regulation of FGFR4 signaling / Negative regulation of FGFR1 signaling / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / B cell receptor signaling pathway / Spry regulation of FGF signaling / peptidyl-threonine phosphorylation / response to nicotine / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / regulation of protein stability / Oncogene Induced Senescence / mitotic spindle / Regulation of actin dynamics for phagocytic cup formation
Similarity search - Function
Mitogen-activated protein (MAP) kinase, ERK1/2 / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / 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. / Protein kinase domain ...Mitogen-activated protein (MAP) kinase, ERK1/2 / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / 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. / 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-390 / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 Å
AuthorsChaikuad, A. / Savitsky, P. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: Nat.Chem.Biol. / Year: 2014
Title: A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics.
Authors: Chaikuad, A. / M C Tacconi, E. / Zimmer, J. / Liang, Y. / Gray, N.S. / Tarsounas, M. / Knapp, S.
History
DepositionJul 7, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 23, 2014Provider: repository / Type: Initial release
Revision 1.1Sep 24, 2014Group: Database references
Revision 1.2Sep 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: Mitogen-activated protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,94931
Polymers41,5321
Non-polymers2,41730
Water8,287460
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Mitogen-activated protein kinase 1
hetero molecules

A: Mitogen-activated protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)87,89862
Polymers83,0632
Non-polymers4,83460
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation5_675x-y+1,-y+2,-z+1/31
Buried area9650 Å2
ΔGint-121 kcal/mol
Surface area33530 Å2
MethodPISA
Unit cell
Length a, b, c (Å)96.729, 96.729, 95.382
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number154
Space group name H-MP3221
Components on special symmetry positions
IDModelComponents
11A-419-

EDO

21A-427-

CL

31A-856-

HOH

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Mitogen-activated protein kinase 1 / MAP kinase 1 / MAPK 1 / ERT1 / Extracellular signal-regulated kinase 2 / ERK-2 / MAP kinase isoform ...MAP kinase 1 / MAPK 1 / ERT1 / Extracellular signal-regulated kinase 2 / ERK-2 / MAP kinase isoform p42 / p42-MAPK / Mitogen-activated protein kinase 2 / MAP kinase 2 / MAPK 2


Mass: 41531.730 Da / Num. of mol.: 1 / Fragment: kinase domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ERK2, MAPK1, PRKM1, PRKM2 / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21-R3-pRARE2
References: UniProt: P28482, mitogen-activated protein kinase

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Non-polymers , 5 types, 490 molecules

#2: Chemical...
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 22 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#5: Chemical ChemComp-390 / 4-{2-[(2-chloro-4-fluorophenyl)amino]-5-methylpyrimidin-4-yl}-N-[(1S)-1-(3-chlorophenyl)-2-hydroxyethyl]-1H-pyrrole-2-carboxamide


Mass: 500.352 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H20Cl2FN5O2
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 460 / 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: 3.1 Å3/Da / Density % sol: 60.34 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 25% PEG smears (PEG2000, PEG3350, PEG4000 and PEG5000MME), 0.1 M cacodylate pH 5.5 and 0.2 M ammonium sulphate, VAPOR DIFFUSION, SITTING DROP, temperature 277.15K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.97949 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Apr 14, 2014 / Details: Kirkpatrick Baez bimorph mirror pair
RadiationMonochromator: Si (111) double crystal monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 1.5→21.57 Å / Num. all: 81004 / Num. obs: 81001 / % possible obs: 98.2 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 7.1 % / Biso Wilson estimate: 17.9 Å2 / Rmerge(I) obs: 0.064 / Net I/σ(I): 15.3
Reflection shellResolution: 1.5→1.58 Å / Redundancy: 7.1 % / Rmerge(I) obs: 0.652 / Mean I/σ(I) obs: 3 / Num. unique all: 11574 / % possible all: 96.9

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Processing

Software
NameVersionClassification
GDAdata collection
PHASERphasing
REFMAC5.8.0069refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb entry 1ERK

1erk
PDB Unreleased entry


Resolution: 1.5→83.77 Å / Cor.coef. Fo:Fc: 0.978 / Cor.coef. Fo:Fc free: 0.972 / SU B: 2.029 / SU ML: 0.04 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 2 / ESU R: 0.053 / ESU R Free: 0.055 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.16709 3995 4.9 %RANDOM
Rwork0.1456 ---
obs0.14667 77002 97.91 %-
all-81001 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 33.32 Å2
Baniso -1Baniso -2Baniso -3
1-0.33 Å20.17 Å20 Å2
2--0.33 Å2-0 Å2
3----1.08 Å2
Refine analyzeLuzzati coordinate error obs: 0.174 Å
Refinement stepCycle: LAST / Resolution: 1.5→83.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2846 0 149 460 3455
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0193154
X-RAY DIFFRACTIONr_bond_other_d0.0020.023047
X-RAY DIFFRACTIONr_angle_refined_deg1.6171.9844258
X-RAY DIFFRACTIONr_angle_other_deg0.82337024
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9675378
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.76624.238151
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.9615544
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.6551519
X-RAY DIFFRACTIONr_chiral_restr0.1070.2459
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0213621
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02718
X-RAY DIFFRACTIONr_mcbond_it1.0371.3321434
X-RAY DIFFRACTIONr_mcbond_other1.0361.3311433
X-RAY DIFFRACTIONr_mcangle_it1.5621.9991802
X-RAY DIFFRACTIONr_mcangle_other1.56221803
X-RAY DIFFRACTIONr_scbond_it2.1771.6961720
X-RAY DIFFRACTIONr_scbond_other2.1761.6961721
X-RAY DIFFRACTIONr_scangle_other2.8862.392445
X-RAY DIFFRACTIONr_long_range_B_refined7.73813.8114010
X-RAY DIFFRACTIONr_long_range_B_other7.7413.8044008
LS refinement shellResolution: 1.5→1.539 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.229 326 -
Rwork0.229 5529 -
obs--96.47 %
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)
11.80870.70830.23182.1218-0.42032.2511-0.03390.24170.1727-0.1197-0.2823-0.5136-0.38650.77090.31620.1541-0.0802-0.01710.32340.1830.226627.137171.278426.7049
20.8211-0.25740.59991.0479-0.69431.7961-0.0135-0.03260.0745-0.0054-0.04480.0503-0.1618-0.01560.05830.04820.0013-0.00850.0051-0.00790.0141.949969.692329.6088
33.37483.265-2.80433.1932-2.8774.73540.2622-0.30630.4580.3072-0.23540.3734-0.9730.6106-0.02680.5478-0.244-0.19720.3820.02150.540426.439184.509139.1543
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A11 - 130
2X-RAY DIFFRACTION2A131 - 325
3X-RAY DIFFRACTION3A326 - 358

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