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- PDB-3i60: Crystal structure of ERK2 bound to (S)-4-(2-(2-chlorophenylamino)... -

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Entry
Database: PDB / ID: 3i60
TitleCrystal structure of ERK2 bound to (S)-4-(2-(2-chlorophenylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-2-carboxamide
ComponentsMitogen-activated protein kinase 1
KeywordsTRANSFERASE / kinase / inhibitor / ATP-binding / Cell cycle / Host-virus interaction / Nucleotide-binding / Phosphoprotein / Serine/threonine-protein kinase
Function / homology
Function and homology information


phospho-PLA2 pathway / Signaling by MAPK mutants / RAF-independent MAPK1/3 activation / Suppression of apoptosis / Gastrin-CREB signalling pathway via PKC and MAPK / Signaling by Activin / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / cytosine metabolic process / Signaling by MAP2K mutants ...phospho-PLA2 pathway / Signaling by MAPK mutants / RAF-independent MAPK1/3 activation / Suppression of apoptosis / Gastrin-CREB signalling pathway via PKC and MAPK / Signaling by Activin / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / cytosine metabolic process / Signaling by MAP2K mutants / Signaling by NODAL / ERKs are inactivated / response to epidermal growth factor / RSK activation / Golgi Cisternae Pericentriolar Stack Reorganization / Regulation of the apoptosome activity / positive regulation of macrophage proliferation / regulation of cellular pH / outer ear morphogenesis / Signaling by LTK in cancer / regulation of Golgi inheritance / labyrinthine layer blood vessel development / ERBB signaling pathway / mammary gland epithelial cell proliferation / trachea formation / Negative feedback regulation of MAPK pathway / positive regulation of peptidyl-threonine phosphorylation / regulation of early endosome to late endosome transport / regulation of stress-activated MAPK cascade / IFNG signaling activates MAPKs / Frs2-mediated activation / ERBB2-ERBB3 signaling pathway / MAPK1 (ERK2) activation / positive regulation of macrophage chemotaxis / Activation of the AP-1 family of transcription factors / regulation of cytoskeleton organization / ERK/MAPK targets / RUNX2 regulates osteoblast differentiation / response to exogenous dsRNA / face development / lung morphogenesis / positive regulation of telomere maintenance / Recycling pathway of L1 / pseudopodium / Bergmann glial cell differentiation / androgen receptor signaling pathway / thyroid gland development / steroid hormone receptor signaling pathway / Advanced glycosylation endproduct receptor signaling / RHO GTPases Activate NADPH Oxidases / MAP kinase activity / negative regulation of cell differentiation / regulation of ossification / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / Regulation of HSF1-mediated heat shock response / RHO GTPases Activate WASPs and WAVEs / JUN kinase activity / mitogen-activated protein kinase / Signal attenuation / Estrogen-stimulated signaling through PRKCZ / phosphatase binding / Schwann cell development / Growth hormone receptor signaling / progesterone receptor signaling pathway / stress-activated MAPK cascade / Nuclear events stimulated by ALK signaling in cancer / NPAS4 regulates expression of target genes / phosphotyrosine residue binding / myelination / RNA polymerase II CTD heptapeptide repeat kinase activity / peptidyl-threonine phosphorylation / Transcriptional and post-translational regulation of MITF-M expression and activity / NCAM signaling for neurite out-growth / ERK1 and ERK2 cascade / cellular response to amino acid starvation / insulin-like growth factor receptor signaling pathway / lipopolysaccharide-mediated signaling pathway / ESR-mediated signaling / thymus development / Regulation of PTEN gene transcription / Signal transduction by L1 / B cell receptor signaling pathway / FCGR3A-mediated phagocytosis / FCERI mediated MAPK activation / response to nicotine / Negative regulation of FGFR3 signaling / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling / Downregulation of SMAD2/3:SMAD4 transcriptional activity / Negative regulation of FGFR1 signaling / positive regulation of cholesterol biosynthetic process / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / Spry regulation of FGF signaling / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / regulation of protein stability / Oncogene Induced Senescence / caveola / Regulation of actin dynamics for phagocytic cup formation / long-term synaptic potentiation
Similarity search - Function
Mitogen-activated protein (MAP) kinase, ERK1/2 / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. ...Mitogen-activated protein (MAP) kinase, ERK1/2 / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-E86 / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.5 Å
AuthorsJacobs, M.D. / Xie, X.
CitationJournal: J.Med.Chem. / Year: 2009
Title: Structure-guided design of potent and selective pyrimidylpyrrole inhibitors of extracellular signal-regulated kinase (ERK) using conformational control.
Authors: Aronov, A.M. / Tang, Q. / Martinez-Botella, G. / Bemis, G.W. / Cao, J. / Chen, G. / Ewing, N.P. / Ford, P.J. / Germann, U.A. / Green, J. / Hale, M.R. / Jacobs, M. / Janetka, J.W. / Maltais, ...Authors: Aronov, A.M. / Tang, Q. / Martinez-Botella, G. / Bemis, G.W. / Cao, J. / Chen, G. / Ewing, N.P. / Ford, P.J. / Germann, U.A. / Green, J. / Hale, M.R. / Jacobs, M. / Janetka, J.W. / Maltais, F. / Markland, W. / Namchuk, M.N. / Nanthakumar, S. / Poondru, S. / Straub, J. / ter Haar, E. / Xie, X.
History
DepositionJul 6, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 12, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Refinement description / Version format compliance
Revision 1.2Nov 1, 2017Group: Refinement description / Category: software
Revision 1.3Feb 21, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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
Revision 1.4Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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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)44,3525
Polymers43,6161
Non-polymers7364
Water2,360131
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)44.061, 70.251, 119.598
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 43616.008 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ERK2, MAPK1, PRKM1, PRKM2 / Plasmid: pT7BLUE / Production host: Escherichia coli (E. coli) / Strain (production host): BL21
References: UniProt: P28482, mitogen-activated protein kinase
#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-E86 / 4-{2-[(2-chlorophenyl)amino]-5-methylpyrimidin-4-yl}-N-[(1S)-2-hydroxy-1-phenylethyl]-1H-pyrrole-2-carboxamide


Mass: 447.917 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H22ClN5O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 131 / 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: 2.12 Å3/Da / Density % sol: 42.03 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.2
Details: Protein: 14 mg/ml, 20 mM Tris-HCl pH 7.0, 5 mM DTT, 200 mM NaCl. Precipitant: 100 mM HEPES pH 7.2, 28-30% PEG MME 2000, 200 mM Ammonium sulfate, 20 mM 2-Mercaptoethanol, VAPOR DIFFUSION, ...Details: Protein: 14 mg/ml, 20 mM Tris-HCl pH 7.0, 5 mM DTT, 200 mM NaCl. Precipitant: 100 mM HEPES pH 7.2, 28-30% PEG MME 2000, 200 mM Ammonium sulfate, 20 mM 2-Mercaptoethanol, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.54 Å
DetectorType: RIGAKU RAXIS / Detector: IMAGE PLATE / Date: Nov 15, 2001 / Details: Yale mirrors
RadiationMonochromator: Ni FILTER / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.5→55 Å / Num. obs: 12882 / % possible obs: 95.5 % / Rmerge(I) obs: 0.056 / Χ2: 1.365 / Net I/σ(I): 19.3
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.5-2.570.32910021.263192
2.57-2.660.25710211.199192.6
2.66-2.750.21410321.422192.7
2.75-2.860.17210131.287194.1
2.86-2.990.13810561.293194.8
2.99-3.150.09810461.243193.5
3.15-3.350.07710851.228198
3.35-3.610.05710651.216196.7
3.61-3.970.04411031.378197.4
3.97-4.540.03511091.486197.6
4.54-5.720.03211281.552198.3
5.72-550.02412221.702198

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT3.005data extraction
CNSphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: in-house unpublished structure

Resolution: 2.5→55 Å / Cor.coef. Fo:Fc: 0.928 / Cor.coef. Fo:Fc free: 0.893 / WRfactor Rfree: 0.243 / WRfactor Rwork: 0.202 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.846 / SU B: 17.265 / SU ML: 0.182 / SU R Cruickshank DPI: 0.282 / SU Rfree: 0.329 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.329 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: 1. HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. 2. U VALUES: RESIDUAL ONLY.
RfactorNum. reflection% reflectionSelection details
Rfree0.248 1014 8.1 %RANDOM
Rwork0.207 ---
obs0.211 12498 92.98 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 69.46 Å2 / Biso mean: 23.63 Å2 / Biso min: 3.29 Å2
Baniso -1Baniso -2Baniso -3
1-0.12 Å20 Å20 Å2
2---0.04 Å20 Å2
3----0.08 Å2
Refinement stepCycle: LAST / Resolution: 2.5→55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2732 0 47 131 2910
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0222843
X-RAY DIFFRACTIONr_angle_refined_deg1.0531.9933852
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1725332
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.63324.074135
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.88915502
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.2961518
X-RAY DIFFRACTIONr_chiral_restr0.0740.2417
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0212150
X-RAY DIFFRACTIONr_mcbond_it0.5471.51677
X-RAY DIFFRACTIONr_mcangle_it1.03322720
X-RAY DIFFRACTIONr_scbond_it1.27731166
X-RAY DIFFRACTIONr_scangle_it2.194.51132
LS refinement shellResolution: 2.5→2.56 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.312 66 -
Rwork0.262 765 -
all-831 -
obs--85.14 %
Refinement TLS params.Method: refined / Origin x: 15.3815 Å / Origin y: 2.9797 Å / Origin z: 39.7697 Å
111213212223313233
T0.0404 Å2-0.0007 Å2-0.0018 Å2-0.0168 Å2-0.007 Å2--0.0328 Å2
L0.6836 °2-0.1608 °2-0.2221 °2-0.3121 °2-0.63 °2--1.9066 °2
S0.0137 Å °-0.0662 Å °-0.0099 Å °-0.015 Å °-0.0337 Å °0.002 Å °-0.0461 Å °0.1384 Å °0.0201 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A6 - 356
2X-RAY DIFFRACTION1A401 - 404
3X-RAY DIFFRACTION1A359 - 493

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