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- PDB-4xp0: Crystal structure of ERK2 in complex with an inhibitor -

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Basic information

Entry
Database: PDB / ID: 4xp0
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 / Transcriptional and post-translational regulation of MITF-M expression and activity / Negative feedback regulation of MAPK pathway ...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 / Transcriptional and post-translational regulation of MITF-M expression and activity / Negative feedback regulation of MAPK pathway / Gastrin-CREB signalling pathway via PKC and MAPK / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / IFNG signaling activates MAPKs / Golgi Cisternae Pericentriolar Stack Reorganization / RHO GTPases Activate WASPs and WAVEs / 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 / Regulation of actin dynamics for phagocytic cup formation / 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 / Signaling by Activin / Negative regulation of FGFR2 signaling / Signal transduction by L1 / RHO GTPases Activate NADPH Oxidases / Negative regulation of MAPK pathway / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Interferon gamma signaling / FCERI mediated MAPK activation / Regulation of HSF1-mediated heat shock response / diadenosine tetraphosphate biosynthetic process / MAP2K and MAPK activation / neural crest cell development / Recycling pathway of L1 / cellular response to toxic substance / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / cytosine metabolic process / mitogen-activated protein kinase kinase kinase binding / cellular response to methionine / response to epidermal growth factor / positive regulation of macrophage proliferation / response to alcohol / regulation of cellular pH / outer ear morphogenesis / regulation of Golgi inheritance / labyrinthine layer blood vessel development / RAF/MAP kinase cascade / Thrombin signalling through proteinase activated receptors (PARs) / ERBB signaling pathway / Neutrophil degranulation / mammary gland epithelial cell proliferation / trachea formation / regulation of early endosome to late endosome transport / regulation of stress-activated MAPK cascade / cellular response to insulin-like growth factor stimulus / ERBB2-ERBB3 signaling pathway / positive regulation of macrophage chemotaxis / regulation of cytoskeleton organization / response to exogenous dsRNA / face development / lung morphogenesis / positive regulation of telomere maintenance / response to testosterone / pseudopodium / Bergmann glial cell differentiation / androgen receptor signaling pathway / thyroid gland development / steroid hormone receptor signaling pathway / decidualization / MAP kinase activity / negative regulation of cell differentiation / regulation of ossification / JUN kinase activity / mitogen-activated protein kinase / phosphatase binding / Schwann cell development / progesterone receptor signaling pathway / stress-activated MAPK cascade / estrous cycle / positive regulation of cardiac muscle cell proliferation / cellular response to platelet-derived growth factor stimulus / cellular response to cAMP / sensory perception of pain / dendrite cytoplasm / phosphotyrosine residue binding / myelination / RNA polymerase II CTD heptapeptide repeat kinase activity / peptidyl-threonine phosphorylation / ERK1 and ERK2 cascade / cellular response to epidermal growth factor stimulus
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
1H-pyrrolo[2,3-b]pyridine-3-carbonitrile / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.46 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 2.0Sep 6, 2017Group: Advisory / Atomic model ...Advisory / Atomic model / Author supporting evidence / Data collection / Derived calculations
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / diffrn_radiation_wavelength / pdbx_audit_support / pdbx_distant_solvent_atoms / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.label_alt_id / _atom_site.occupancy / _atom_site_anisotrop.U[1][1] / _atom_site_anisotrop.U[1][2] / _atom_site_anisotrop.U[1][3] / _atom_site_anisotrop.U[2][2] / _atom_site_anisotrop.U[2][3] / _atom_site_anisotrop.U[3][3] / _atom_site_anisotrop.pdbx_label_alt_id / _pdbx_audit_support.funding_organization / _pdbx_distant_solvent_atoms.auth_seq_id / _struct_site_gen.auth_seq_id
Revision 2.1Nov 6, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature
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)41,4735
Polymers41,0771
Non-polymers3954
Water6,413356
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area530 Å2
ΔGint-10 kcal/mol
Surface area16350 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.910, 70.790, 60.410
Angle α, β, γ (deg.)90.000, 108.990, 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: 41077.367 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-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-42A / 1H-pyrrolo[2,3-b]pyridine-3-carbonitrile


Mass: 143.145 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H5N3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 356 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.42 Å3/Da / Density % sol: 49.19 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 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: ID23-2 / Wavelength: 0.8726 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Nov 3, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8726 Å / Relative weight: 1
ReflectionResolution: 1.46→28.631 Å / Num. all: 64331 / Num. obs: 64331 / % possible obs: 95.4 % / Redundancy: 2.2 % / Biso Wilson estimate: 19.29 Å2 / Rmerge(I) obs: 0.031 / Rpim(I) all: 0.033 / Rrim(I) all: 0.049 / Rsym value: 0.031 / Net I/av σ(I): 8.081 / Net I/σ(I): 9.5 / Num. measured all: 144557
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRpim(I) allRsym valueNet I/σ(I) obs% possible all
1.46-1.542.20.481.51824584240.4850.481.385.7
1.54-1.632.20.3122.31971888790.3190.3122.195.6
1.63-1.752.20.1674.31868383790.1780.1673.496.1
1.75-1.882.30.0937.71773878490.1010.0935.696.5
1.88-2.062.20.055121624372680.060.0559.497.1
2.06-2.312.30.03518.41492665940.0390.03513.797.5
2.31-2.672.30.02817.21346258790.0280.02817.297.9
2.67-3.262.30.02225.31161350010.0220.02220.698.4
3.26-4.622.30.01930899838870.020.01923.798.6
4.62-28.8592.30.02810.2493121710.030.02824.698.6

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Processing

Software
NameVersionClassification
SCALA3.2.19data scaling
PHENIXrefinement
PDB_EXTRACT3.15data extraction
PHENIXphasing
RefinementResolution: 1.46→28.631 Å / SU ML: 0.24 / Cross valid method: FREE R-VALUE / σ(F): 1.31 / Phase error: 23.32 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.214 5500 5.02 %
Rwork0.1904 104028 -
obs0.1916 64302 82.28 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 64.314 Å2 / ksol: 0.351 e/Å3
Displacement parametersBiso max: 87.49 Å2 / Biso mean: 26.8502 Å2 / Biso min: 8.61 Å2
Baniso -1Baniso -2Baniso -3
1--0.4309 Å2-0 Å2-0.2697 Å2
2--0.8024 Å2-0 Å2
3----0.3715 Å2
Refinement stepCycle: final / Resolution: 1.46→28.631 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2782 0 24 356 3162
Biso mean--34.91 37.33 -
Num. residues----340
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0142989
X-RAY DIFFRACTIONf_angle_d1.14051
X-RAY DIFFRACTIONf_chiral_restr0.076454
X-RAY DIFFRACTIONf_plane_restr0.006508
X-RAY DIFFRACTIONf_dihedral_angle_d13.4531174
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.46-1.47660.3951370.39372441257858
1.4766-1.4940.41941560.39582702285864
1.494-1.51220.4451590.38463179333876
1.5122-1.53140.35611560.36133349350578
1.5314-1.55150.37431710.34093294346579
1.5515-1.57280.35631680.32413355352379
1.5728-1.59520.34522210.31253339356080
1.5952-1.6190.32431830.29763340352379
1.619-1.64430.33771850.28183387357280
1.6443-1.67130.29551930.26143382357581
1.6713-1.70010.28381530.24493448360181
1.7001-1.7310.241890.23083433362282
1.731-1.76430.24561870.21863452363982
1.7643-1.80030.21571560.21033498365483
1.8003-1.83940.22971750.19923533370883
1.8394-1.88220.21591620.19923521368383
1.8822-1.92930.23981530.19823519367283
1.9293-1.98140.23821990.18673525372484
1.9814-2.03970.19981460.18273613375984
2.0397-2.10550.19641750.17253547372285
2.1055-2.18080.19112160.16973576379286
2.1808-2.26810.17962160.18163553376985
2.2681-2.37120.21851930.18123630382386
2.3712-2.49620.22962130.17643626383987
2.4962-2.65250.18812320.17163679391188
2.6525-2.85710.20512130.17643746395989
2.8571-3.14430.18321950.16813728392389
3.1443-3.59850.21571760.16653829400590
3.5985-4.53090.15472250.14593860408592
4.5309-28.63650.21821970.19383944414193
Refinement TLS params.Method: refined / Origin x: -4.3706 Å / Origin y: 5.6043 Å / Origin z: 48.3292 Å
111213212223313233
T0.0659 Å2-0.0035 Å20.0108 Å2-0.0964 Å20.0267 Å2--0.1017 Å2
L0.5986 °20.2456 °20.2897 °2-0.3794 °20.2926 °2--0.8474 °2
S-0.0507 Å °0.0735 Å °0.0827 Å °-0.0643 Å °0.0478 Å °-0.0111 Å °-0.077 Å °0.0477 Å °-0.0007 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA8 - 354
2X-RAY DIFFRACTION1allA1 - 264
3X-RAY DIFFRACTION1allD9 - 12
4X-RAY DIFFRACTION1allB1
5X-RAY DIFFRACTION1allS1 - 380

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