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

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Basic information

Entry
Database: PDB / ID: 4xoy
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
2-amino-1,9-dihydro-6H-purine-6-thione / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MIR / Resolution: 2.1 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 / Derived calculations
Category: atom_site / pdbx_audit_support ...atom_site / pdbx_audit_support / pdbx_distant_solvent_atoms / pdbx_validate_close_contact / 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 / _pdbx_audit_support.funding_organization / _pdbx_distant_solvent_atoms.auth_seq_id / _pdbx_validate_close_contact.auth_seq_id_1 / _pdbx_validate_close_contact.auth_seq_id_2 / _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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Mitogen-activated protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,3413
Polymers41,0771
Non-polymers2632
Water2,576143
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area180 Å2
ΔGint-12 kcal/mol
Surface area16120 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.178, 71.417, 61.263
Angle α, β, γ (deg.)90.00, 109.51, 90.00
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 / Fragment: UNP residues 8-358
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-DX4 / 2-amino-1,9-dihydro-6H-purine-6-thione / Tioguanine


Mass: 167.192 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C5H5N5S / Comment: medication*YM
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: SO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 143 / 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: 2.48 Å3/Da / Density % sol: 50.4 %
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: 298 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: BM30A / Wavelength: 0.97922 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 21, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97922 Å / Relative weight: 1
ReflectionResolution: 2.1→29.305 Å / Num. obs: 28103 / % possible obs: 89.8 % / Redundancy: 2.5 % / Net I/σ(I): 6
Reflection shellResolution: 2.1→2.15 Å / Rmerge(I) obs: 0.514 / Mean I/σ(I) obs: 1.95 / % possible all: 67.8

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Processing

Software
NameVersionClassification
PHENIX(phenix.refine: 1.9_1692)refinement
XDSdata reduction
PDB_EXTRACT3.15data extraction
XSCALEdata scaling
REFMACphasing
RefinementMethod to determine structure: MIR
Starting model: Isomorphous replacement with a simple Rigid Body with Refmac5, using another structure of the same proteine (3QYW)

3qyw


Resolution: 2.1→29.287 Å / SU ML: 0.24 / Cross valid method: FREE R-VALUE / σ(F): 0.88 / Phase error: 22.67 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2185 3411 9.46 %
Rwork0.1787 --
obs0.1825 36039 78.59 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.1→29.287 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2687 0 16 143 2846
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082785
X-RAY DIFFRACTIONf_angle_d1.1243767
X-RAY DIFFRACTIONf_dihedral_angle_d14.9761048
X-RAY DIFFRACTIONf_chiral_restr0.043415
X-RAY DIFFRACTIONf_plane_restr0.006477
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.130.29621060.2794946X-RAY DIFFRACTION55
2.13-2.16180.2872850.2558970X-RAY DIFFRACTION56
2.1618-2.19560.2746930.2412942X-RAY DIFFRACTION55
2.1956-2.23150.27851450.21041504X-RAY DIFFRACTION83
2.2315-2.270.28771600.20591397X-RAY DIFFRACTION83
2.27-2.31130.26391520.19931457X-RAY DIFFRACTION85
2.3113-2.35570.25181360.19081475X-RAY DIFFRACTION83
2.3557-2.40380.2411680.19061433X-RAY DIFFRACTION85
2.4038-2.4560.22711450.18811454X-RAY DIFFRACTION83
2.456-2.51310.21911620.18041386X-RAY DIFFRACTION84
2.5131-2.57590.23211650.18291434X-RAY DIFFRACTION83
2.5759-2.64550.26061590.17971431X-RAY DIFFRACTION83
2.6455-2.72330.24531330.18451442X-RAY DIFFRACTION83
2.7233-2.81120.21541420.18691432X-RAY DIFFRACTION82
2.8112-2.91150.2171620.18241414X-RAY DIFFRACTION82
2.9115-3.0280.24131470.18661415X-RAY DIFFRACTION82
3.028-3.16570.21641550.17921369X-RAY DIFFRACTION82
3.1657-3.33230.23171480.17641457X-RAY DIFFRACTION82
3.3323-3.54080.22181340.16771402X-RAY DIFFRACTION81
3.5408-3.81360.19541560.15721395X-RAY DIFFRACTION80
3.8136-4.19640.15081410.14671391X-RAY DIFFRACTION81
4.1964-4.80140.17721340.14711414X-RAY DIFFRACTION80
4.8014-6.04050.19561460.17521376X-RAY DIFFRACTION79
6.0405-29.28970.23641370.19391292X-RAY DIFFRACTION75
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)
10.0019-0.00740.0028-0.0003-0.00050.0033-0.0079-0.03940.0458-0.01510.05410.078-0.0222-0.058-00.08140.0148-0.03520.12440.0773-0.1-15.098712.424835.7518
20.03130.01080.01230.0503-0.01280.02630.00360.00260.04410.00220.00150.00880.0220.009400.0501-0.00240.00210.0490.00750.0675-0.25766.520455.2666
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 9 through 120 )
2X-RAY DIFFRACTION2chain 'A' and (resid 121 through 353 )

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