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

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Basic information

Entry
Database: PDB / ID: 4xoz
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 / 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 / Oxidative Stress Induced Senescence / 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 / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / cytosine metabolic process / response to epidermal growth factor / cellular response to methionine / cellular response to toxic substance / positive regulation of macrophage proliferation / regulation of cellular pH / outer ear morphogenesis / regulation of Golgi inheritance / RAF/MAP kinase cascade / mitogen-activated protein kinase kinase kinase binding / response to alcohol / ERBB signaling pathway / Thrombin signalling through proteinase activated receptors (PARs) / labyrinthine layer blood vessel development / mammary gland epithelial cell proliferation / trachea formation / Neutrophil degranulation / regulation of early endosome to late endosome transport / regulation of stress-activated MAPK cascade / steroid hormone receptor signaling pathway / cellular response to insulin-like growth factor stimulus / androgen receptor signaling pathway / positive regulation of macrophage chemotaxis / ERBB2-ERBB3 signaling pathway / response to testosterone / regulation of cytoskeleton organization / response to exogenous dsRNA / pseudopodium / lung morphogenesis / face development / positive regulation of telomere maintenance / Bergmann glial cell differentiation / decidualization / thyroid gland development / peptidyl-threonine phosphorylation / progesterone receptor signaling pathway / regulation of ossification / MAP kinase activity / negative regulation of cell differentiation / mitogen-activated protein kinase / phosphatase binding / Schwann cell development / estrous cycle / stress-activated MAPK cascade / positive regulation of cardiac muscle cell proliferation / cellular response to platelet-derived growth factor stimulus / ERK1 and ERK2 cascade / phosphotyrosine residue binding / myelination / sensory perception of pain / RNA polymerase II CTD heptapeptide repeat kinase activity / dendrite cytoplasm / insulin-like growth factor receptor signaling pathway / cellular response to amino acid starvation / lipopolysaccharide-mediated signaling pathway
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-620 / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 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: Atomic model / Author supporting evidence ...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 / 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_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] / _pdbx_audit_support.funding_organization / _struct_site_gen.auth_seq_id
Revision 2.1Jan 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
Revision 2.2Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)41,2413
Polymers40,8491
Non-polymers3922
Water2,540141
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area180 Å2
ΔGint-13 kcal/mol
Surface area16720 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.170, 71.550, 60.890
Angle α, β, γ (deg.)90.000, 108.600, 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: 40849.012 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-620 / N~1~-[3-(benzyloxy)benzyl]-1H-tetrazole-1,5-diamine


Mass: 296.327 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H16N6O
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 141 / 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: 2.49 Å3/Da / Density % sol: 50.51 %
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: ID14-2 / Wavelength: 0.933 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Apr 23, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.933 Å / Relative weight: 1
ReflectionResolution: 1.95→29.025 Å / Num. all: 27177 / Num. obs: 27177 / % possible obs: 93.1 % / Redundancy: 2.6 % / Biso Wilson estimate: 28.7 Å2 / Rmerge(I) obs: 0.023 / Rpim(I) all: 0.023 / Rrim(I) all: 0.038 / Rsym value: 0.023 / Net I/av σ(I): 18.803 / Net I/σ(I): 13.5 / Num. measured all: 69568
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
1.95-2.062.40.2093.8751931530.2010.2092.375.2
2.06-2.182.60.1156.9997838590.1030.1154.296
2.18-2.332.60.07510.5970336730.0710.0756.396.9
2.33-2.522.60.05214.9898234090.0470.0529.196.8
2.52-2.762.50.03520.1806831670.0350.03512.697.2
2.76-3.082.60.02525725428420.0250.02517.396.9
3.08-3.562.60.01736.4639324880.0190.01723.796
3.56-4.362.60.01633.3546421120.0150.01629.395.7
4.36-6.172.50.01538.9406816100.0140.01531.194
6.17-31.6542.50.01527.421398640.0130.01534.290.7

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Processing

Software
NameVersionClassification
PHENIXrefinement
PDB_EXTRACT3.15data extraction
SCALAdata scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3QYW

3qyw


Resolution: 1.95→28.949 Å / SU ML: 0.17 / Cross valid method: FREE R-VALUE / σ(F): 1.26 / Phase error: 18.42 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1883 2515 5.11 %
Rwork0.1452 46663 -
obs0.1474 27176 85.75 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 105.95 Å2 / Biso mean: 35.4385 Å2 / Biso min: 13.2 Å2
Refinement stepCycle: final / Resolution: 1.95→28.949 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2798 0 27 141 2966
Biso mean--43.43 43.15 -
Num. residues----342
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0122927
X-RAY DIFFRACTIONf_angle_d1.4243967
X-RAY DIFFRACTIONf_chiral_restr0.062438
X-RAY DIFFRACTIONf_plane_restr0.007504
X-RAY DIFFRACTIONf_dihedral_angle_d14.3541114
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 (%)
1.95-1.98750.2682800.24141754183458
1.9875-2.02810.281870.22652023211066
2.0281-2.07220.2428940.19372403249779
2.0722-2.12040.21641360.18032680281688
2.1204-2.17340.1971760.17212723289991
2.1734-2.23210.20641780.16372728290691
2.2321-2.29780.1941490.16772731288092
2.2978-2.37190.21891610.16462726288791
2.3719-2.45670.23621480.16642743289190
2.4567-2.5550.20811620.15652725288790
2.555-2.67120.19341730.15692709288291
2.6712-2.81190.22241510.15222726287790
2.8119-2.98790.20051420.15552702284490
2.9879-3.21830.17061390.14342725286489
3.2183-3.54170.18321330.14022666279989
3.5417-4.0530.17631260.11582708283489
4.053-5.10170.15871580.11412625278387
5.1017-28.95210.15381220.1352566268885
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)
10.56190.0274-0.97260.0615-0.07673.1190.02650.26160.2481-0.1210.07080.0783-0.4224-0.4985-0.0920.32680.011-0.03540.33370.05530.2574-13.512812.723134.5441
22.17730.97971.03720.76830.24121.3591-0.01340.05720.1375-0.00170.0134-0.0365-0.08260.0917-0.00320.12670.01620.01920.09760.00080.1511.62917.99858.3074
30.778-0.102-0.02381.5051-1.80523.27350.00490.2078-0.0269-0.2692-0.2581-0.10360.30560.44190.13470.2589-0.01350.01230.2757-0.01330.2503-4.41470.292635.1931
40.91220.0893-0.12170.52250.0580.8725-0.0303-0.0410.0135-0.0450.0308-0.02050.05950.008-0.00270.2351-0.00720.00380.21020.01980.2395-2.2086.145251.6357
51.01650.47650.98093.5175-0.92991.53070.42750.07660.23650.07070.25370.0026-0.19580.0726-0.60880.6844-0.04880.10570.3098-0.01260.2629-12.538511.995938.5255
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 - 172
5X-RAY DIFFRACTION5chain BB1

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