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- PDB-4xp2: Crystal structure of ERK2 in complex with an inhibitor -

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Basic information

Entry
Database: PDB / ID: 4xp2
TitleCrystal structure of ERK2 in complex with an inhibitor
ComponentsMitogen-activated protein kinase 1
KeywordsTRANSFERASE / SERINE/THREONINE-PROTEIN KINASE
Function / homology
Function and homology information


phospho-PLA2 pathway / RAF-independent MAPK1/3 activation / MAPK1 (ERK2) activation / Signaling by NODAL / Frs2-mediated activation / ERK/MAPK targets / ERKs are inactivated / Activation of the AP-1 family of transcription factors / RHO GTPases Activate WASPs and WAVEs / IFNG signaling activates MAPKs ...phospho-PLA2 pathway / RAF-independent MAPK1/3 activation / MAPK1 (ERK2) activation / Signaling by NODAL / Frs2-mediated activation / ERK/MAPK targets / ERKs are inactivated / Activation of the AP-1 family of transcription factors / RHO GTPases Activate WASPs and WAVEs / IFNG signaling activates MAPKs / Negative feedback regulation of MAPK pathway / Gastrin-CREB signalling pathway via PKC and MAPK / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / Golgi Cisternae Pericentriolar Stack Reorganization / Regulation of actin dynamics for phagocytic cup formation / Estrogen-stimulated signaling through PRKCZ / Growth hormone receptor signaling / Spry regulation of FGF signaling / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / Oxidative Stress Induced Senescence / Senescence-Associated Secretory Phenotype (SASP) / Oncogene Induced Senescence / Signaling by Activin / Downregulation of SMAD2/3:SMAD4 transcriptional activity / Signal attenuation / NCAM signaling for neurite out-growth / Negative regulation of FGFR1 signaling / Negative regulation of FGFR3 signaling / Negative regulation of FGFR4 signaling / Regulation of the apoptosome activity / Signal transduction by L1 / Negative regulation of FGFR2 signaling / RHO GTPases Activate NADPH Oxidases / Negative regulation of MAPK pathway / Interferon gamma signaling / FCERI mediated MAPK activation / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Regulation of HSF1-mediated heat shock response / MAP2K and MAPK activation / diadenosine tetraphosphate biosynthetic process / Recycling pathway of L1 / neural crest cell development / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / cytosine metabolic process / response to epidermal growth factor / mitogen-activated protein kinase kinase kinase binding / regulation of cellular pH / positive regulation of macrophage proliferation / outer ear morphogenesis / Thrombin signalling through proteinase activated receptors (PARs) / RAF/MAP kinase cascade / regulation of Golgi inheritance / ERBB signaling pathway / labyrinthine layer blood vessel development / Neutrophil degranulation / mammary gland epithelial cell proliferation / trachea formation / regulation of early endosome to late endosome transport / : / regulation of stress-activated MAPK cascade / positive regulation of macrophage chemotaxis / lung morphogenesis / ERBB2-ERBB3 signaling pathway / response to exogenous dsRNA / regulation of cytoskeleton organization / face development / androgen receptor signaling pathway / pseudopodium / progesterone receptor signaling pathway / negative regulation of cell differentiation / Bergmann glial cell differentiation / positive regulation of telomere capping / thyroid gland development / decidualization / steroid hormone mediated signaling pathway / MAP kinase activity / regulation of ossification / mitogen-activated protein kinase / phosphatase binding / Schwann cell development / stress-activated MAPK cascade / lipopolysaccharide-mediated signaling pathway / positive regulation of cardiac muscle cell proliferation / sensory perception of pain / cellular response to cadmium ion / positive regulation of telomere maintenance via telomerase / ERK1 and ERK2 cascade / cellular response to amino acid starvation / myelination / dendrite cytoplasm / phosphotyrosine residue binding / RNA polymerase II CTD heptapeptide repeat kinase activity / insulin-like growth factor receptor signaling pathway / thymus development / positive regulation of peptidyl-threonine phosphorylation / caveola / positive regulation of translation / long-term synaptic potentiation / animal organ morphogenesis
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
1-phenyl-1H-1,2,4-triazole-3,5-diamine / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.748 Å
AuthorsGelin, M. / Allemand, F. / Labesse, G. / Guichou, J.F.
Funding support France, 1items
OrganizationGrant numberCountry
French National Research AgencyANR-10-INSB-05-01 France
CitationJournal: Acta Crystallogr.,Sect.D / Year: 2015
Title: Combining `dry' co-crystallization and in situ diffraction to facilitate ligand screening by X-ray crystallography.
Authors: Gelin, M. / Delfosse, V. / Allemand, F. / Hoh, F. / Sallaz-Damaz, Y. / Pirocchi, M. / Bourguet, W. / Ferrer, J.L. / Labesse, G. / Guichou, J.F.
History
DepositionJan 16, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Aug 12, 2015Provider: repository / Type: Initial release
Revision 1.1Aug 19, 2015Group: Database references
Revision 1.2Sep 6, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Jan 10, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)41,4496
Polymers40,9251
Non-polymers5245
Water4,918273
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area790 Å2
ΔGint-20 kcal/mol
Surface area16200 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.637, 70.314, 59.827
Angle α, β, γ (deg.)90.000, 108.930, 90.000
Int Tables number4
Space group name H-MP1211
Detailsbiological unit is the same as asym.

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Components

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


Mass: 40925.129 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Mapk1, Erk2, Mapk, Prkm1 / Production host: Escherichia coli (E. coli)
References: UniProt: P63086, mitogen-activated protein kinase
#2: Chemical ChemComp-TT4 / 1-phenyl-1H-1,2,4-triazole-3,5-diamine


Mass: 175.191 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H9N5
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 273 / 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: 2.37 Å3/Da / Density % sol: 48.17 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 26% PEG MME 2000, 0.1M MES pH 6.5, 0.1M ammonium sulfate, 0.02M beta-mercaptoethanol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: BM30A / Wavelength: 0.9797 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: May 19, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9797 Å / Relative weight: 1
ReflectionResolution: 1.74→28.5 Å / Num. obs: 69472 / % possible obs: 89.7 % / Redundancy: 1.8 % / Rmerge(I) obs: 0.035 / Net I/σ(I): 11.9
Reflection shellResolution: 1.74→1.83 Å / Redundancy: 1.8 % / Rmerge(I) obs: 0.289 / Mean I/σ(I) obs: 1.4 / % possible all: 89.6

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Processing

Software
NameVersionClassification
MOSFLMdata reduction
SCALAdata scaling
PHENIX1.6.4_486refinement
PDB_EXTRACT3.15data extraction
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3qyw

3qyw


Resolution: 1.748→28.295 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 1.12 / Phase error: 22.5 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2263 2503 4.93 %
Rwork0.1852 48312 -
obs0.1873 50815 66.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 53.964 Å2 / ksol: 0.347 e/Å3
Displacement parametersBiso max: 90.64 Å2 / Biso mean: 28.6376 Å2 / Biso min: 4.81 Å2
Baniso -1Baniso -2Baniso -3
1--0.3077 Å20 Å2-0.0887 Å2
2--2.2158 Å20 Å2
3----1.9082 Å2
Refinement stepCycle: final / Resolution: 1.748→28.295 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2773 0 36 273 3082
Biso mean--44.52 35.58 -
Num. residues----339
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082933
X-RAY DIFFRACTIONf_angle_d0.9513970
X-RAY DIFFRACTIONf_chiral_restr0.064435
X-RAY DIFFRACTIONf_plane_restr0.004502
X-RAY DIFFRACTIONf_dihedral_angle_d13.641133
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 18

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.748-1.78160.3861270.37552657278466
1.7816-1.8180.37041480.33952839298770
1.818-1.85750.33641190.2872787290669
1.8575-1.90070.32111280.26812788291670
1.9007-1.94820.34481430.24732774291769
1.9482-2.00090.29591330.21812762289569
2.0009-2.05970.25511210.19632777289869
2.0597-2.12620.22121620.19462727288968
2.1262-2.20220.24381670.17462719288668
2.2022-2.29030.2221270.18792684281168
2.2903-2.39450.25931640.17322701286568
2.3945-2.52070.23351470.17112708285567
2.5207-2.67850.23331560.17222628278466
2.6785-2.88510.22911460.17712580272664
2.8851-3.17510.21121290.17662619274865
3.1751-3.63370.20571220.16822511263363
3.6337-4.5750.15431380.14122429256761
4.575-28.29910.20851260.17882622274865
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)
10.55140.30020.05720.21660.39731.8662-0.10930.17560.1235-0.21720.14220.0795-0.398-0.202-0.00550.2668-0.0046-0.04280.18910.05710.1372-13.620712.277434.1932
20.77580.55460.61460.47810.31470.97340.00410.00190.04860.02640.02060.00660.00960.0506-0.02440.10440.00690.00940.11150.00140.14111.20677.909857.3453
30.51620.00430.76470.7708-0.11521.2497-0.02920.2273-0.062-0.30130.0652-0.00830.39680.4825-0.070.1961-0.03430.02950.2413-0.0320.1628-5.332-0.637135.5849
40.1888-0.01060.1730.44150.10310.6176-0.0297-0.0043-0.0203-0.02240.0408-0.0072-0.02060.0291-0.00720.1584-0.00630.01030.15860.0070.175-3.06486.299151.0661
57.98496.45776.33765.23894.97126.4828-0.05210.0295-0.0623-0.16550.268-0.1623-0.0484-0.1916-0.16330.5817-0.2131-0.0260.6779-0.01920.2131-16.015313.763641.3115
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1(chain A and resid 9:118)A9 - 118
2X-RAY DIFFRACTION2(chain A and resid 119:312)A119 - 312
3X-RAY DIFFRACTION3(chain A and resid 313:354)A313 - 354
4X-RAY DIFFRACTION4chain SS1 - 315
5X-RAY DIFFRACTION5chain BB1

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