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- PDB-2ojg: Crystal structure of ERK2 in complex with N,N-dimethyl-4-(4-pheny... -

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Basic information

Entry
Database: PDB / ID: 2ojg
TitleCrystal structure of ERK2 in complex with N,N-dimethyl-4-(4-phenyl-1H-pyrazol-3-yl)-1H-pyrrole-2-carboxamide
ComponentsMitogen-activated protein kinase 1
KeywordsTRANSFERASE / kinase inhibitor
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-19A / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2 Å
AuthorsXie, X. / Jacobs, M.D.
CitationJournal: J.Med.Chem. / Year: 2007
Title: Flipped Out: Structure-Guided Design of Selective Pyrazolylpyrrole ERK Inhibitors.
Authors: Aronov, A.M. / Baker, C. / Bemis, G.W. / Cao, J. / Chen, G. / Ford, P.J. / Germann, U.A. / Green, J. / Hale, M.R. / Jacobs, M. / Janetka, J.W. / Maltais, F. / Martinez-Botella, G. / Namchuk, ...Authors: Aronov, A.M. / Baker, C. / Bemis, G.W. / Cao, J. / Chen, G. / Ford, P.J. / Germann, U.A. / Green, J. / Hale, M.R. / Jacobs, M. / Janetka, J.W. / Maltais, F. / Martinez-Botella, G. / Namchuk, M.N. / Straub, J. / Tang, Q. / Xie, X.
History
DepositionJan 12, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 6, 2007Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Dec 27, 2023Group: 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

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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)43,9923
Polymers43,6161
Non-polymers3762
Water3,387188
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)48.665, 70.776, 60.141
Angle α, β, γ (deg.)90.00, 109.03, 90.00
Int Tables number4
Space group name H-MP1211

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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: MAPK1, ERK2, PRKM1 / Plasmid: pT7Blue / Production host: Escherichia coli (E. coli)
References: UniProt: P28482, mitogen-activated protein kinase
#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-19A / N,N-DIMETHYL-4-(4-PHENYL-1H-PYRAZOL-3-YL)-1H-PYRROLE-2-CARBOXAMIDE


Mass: 280.324 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H16N4O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 188 / 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: 2.24 Å3/Da / Density % sol: 45.18 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 7.2
Details: protein: 14 mg/ml, 20 mM Tris, 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-ME, VAPOR DIFFUSION, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.5418
DetectorType: RIGAKU / Detector: IMAGE PLATE / Date: Sep 1, 1999
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2→20 Å / Num. obs: 23772 / % possible obs: 93.1 % / Redundancy: 2.77 % / Biso Wilson estimate: 22.1 Å2 / Rmerge(I) obs: 0.048 / Net I/σ(I): 14.8

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Processing

Software
NameVersionClassificationNB
CNSrefinement
PDB_EXTRACT2data extraction
DENZOdata reduction
SCALEPACKdata scaling
CNXphasing
CNX2005refinement
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2→19.97 Å / Rfactor Rfree error: 0.006 / Data cutoff high absF: 766664.688 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.26 2164 9.1 %RANDOM
Rwork0.216 ---
all0.233 23756 --
obs0.22 23756 90.9 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 50.4 Å2 / ksol: 0.349 e/Å3
Displacement parametersBiso mean: 40.4 Å2
Baniso -1Baniso -2Baniso -3
1--5.73 Å20 Å2-1.87 Å2
2--2.6 Å20 Å2
3---3.13 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.3 Å0.24 Å
Luzzati d res low-5 Å
Luzzati sigma a0.17 Å0.14 Å
Refinement stepCycle: LAST / Resolution: 2→19.97 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2756 0 26 188 2970
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.005
X-RAY DIFFRACTIONc_angle_deg1.2
X-RAY DIFFRACTIONc_dihedral_angle_d21.6
X-RAY DIFFRACTIONc_improper_angle_d0.59
X-RAY DIFFRACTIONc_mcbond_it1.361.5
X-RAY DIFFRACTIONc_mcangle_it2.082
X-RAY DIFFRACTIONc_scbond_it2.082
X-RAY DIFFRACTIONc_scangle_it3.022.5
LS refinement shellResolution: 2→2.13 Å / Rfactor Rfree error: 0.018 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.303 299 9.5 %
Rwork0.244 2841 -
obs-3140 72.9 %
Xplor file
Refine-IDSerial noParam file
X-RAY DIFFRACTION1protein_rep.param
X-RAY DIFFRACTION2water_rep.param
X-RAY DIFFRACTION3inhib.par
X-RAY DIFFRACTION4parmxray.xpl
X-RAY DIFFRACTION5ion.param

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