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- PDB-4xp3: Crystal structure of ERK2 in complex with an inhibitor -

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Basic information

Entry
Database: PDB / ID: 4xp3
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
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 / MOLECULAR REPLACEMENT / Resolution: 1.782 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 / atom_site_anisotrop ...atom_site / atom_site_anisotrop / 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 / _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 / _pdbx_distant_solvent_atoms.auth_seq_id / _pdbx_distant_solvent_atoms.neighbor_macromolecule_distance / _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
Revision 2.2Oct 16, 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)42,04814
Polymers40,9251
Non-polymers1,12313
Water8,287460
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1100 Å2
ΔGint-3 kcal/mol
Surface area16300 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.600, 69.683, 59.819
Angle α, β, γ (deg.)90.00, 108.91, 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: 40925.129 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


Mass: 167.192 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H5N5S
#3: Chemical ChemComp-SO4 / SULFATE ION


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


Mass: 78.133 Da / Num. of mol.: 11 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 460 / 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: 2.34 Å3/Da / Density % sol: 47.47 %
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: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.542 Å
DetectorType: MAR scanner 300 mm plate / Detector: IMAGE PLATE / Date: Dec 7, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.542 Å / Relative weight: 1
ReflectionResolution: 1.78→56.6 Å / Num. obs: 55297 / % possible obs: 95.1 % / Redundancy: 2 % / Rmerge(I) obs: 0.037 / Net I/σ(I): 9.1
Reflection shellResolution: 1.78→1.87 Å / Redundancy: 1.8 % / Rmerge(I) obs: 0.149 / Mean I/σ(I) obs: 4.6 / % possible all: 79.9

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Processing

Software
NameVersionClassification
PHENIX(phenix.refine: 1.9_1692)refinement
PDB_EXTRACT3.15data extraction
SCALAdata scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3QYW

3qyw


Resolution: 1.782→23.198 Å / SU ML: 0.14 / Cross valid method: FREE R-VALUE / σ(F): 1.28 / Phase error: 17.07 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.1789 2800 5.06 %Random selection
Rwork0.1488 ---
obs0.1503 55296 77.93 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.782→23.198 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2794 0 60 460 3314
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0093041
X-RAY DIFFRACTIONf_angle_d1.0214116
X-RAY DIFFRACTIONf_dihedral_angle_d13.2731188
X-RAY DIFFRACTIONf_chiral_restr0.043441
X-RAY DIFFRACTIONf_plane_restr0.005523
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7816-1.81230.2637750.2221649X-RAY DIFFRACTION48
1.8123-1.84530.2205980.19642284X-RAY DIFFRACTION67
1.8453-1.88080.26441180.18872419X-RAY DIFFRACTION71
1.8808-1.91910.18861080.17172547X-RAY DIFFRACTION75
1.9191-1.96080.25771430.16252512X-RAY DIFFRACTION76
1.9608-2.00640.19991120.15912595X-RAY DIFFRACTION76
2.0064-2.05660.17521050.15532650X-RAY DIFFRACTION78
2.0566-2.11210.19131650.15972592X-RAY DIFFRACTION78
2.1121-2.17420.18081770.15692580X-RAY DIFFRACTION78
2.1742-2.24440.19871520.15072670X-RAY DIFFRACTION79
2.2444-2.32450.1941500.14572670X-RAY DIFFRACTION80
2.3245-2.41750.18841540.14712732X-RAY DIFFRACTION80
2.4175-2.52740.18431660.14352681X-RAY DIFFRACTION81
2.5274-2.66050.18061750.1452718X-RAY DIFFRACTION82
2.6605-2.82690.1991660.15162787X-RAY DIFFRACTION83
2.8269-3.04470.18291420.1472853X-RAY DIFFRACTION84
3.0447-3.35030.15781490.14052820X-RAY DIFFRACTION85
3.3503-3.83320.14371340.12872916X-RAY DIFFRACTION86
3.8332-4.82230.14591630.12382915X-RAY DIFFRACTION87
4.8223-23.20.181480.17082906X-RAY DIFFRACTION86
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)
10.26610.1481-0.26880.4480.18841.98890.00270.13190.1581-0.17520.13150.1313-0.3206-0.3812-0.09950.20430.0072-0.01760.21860.05750.1672-13.882312.548134.2231
21.26380.63510.63210.62660.23790.98560.0066-0.00530.06210.01110.0044-0.0085-0.04030.0339-0.01660.0770.00910.01020.0570.00190.10140.93057.834157.233
30.37260.2405-0.31571.6091-1.68132.98050.02250.0769-0-0.30640.0401-0.02610.2490.2559-0.07820.1913-0.02690.01010.1662-0.04220.1711-5.2932-0.752735.2749
40.68670.26630.17580.7833-0.12430.7477-0.0156-0.00010.0214-0.02830.04050.0092-0.0246-0.0156-0.02650.12670.00940.0140.1155-0.0050.1408-3.5616.956149.7472
52-0.707-2.50494.38970.8664.19770.0825-0.16850.2631-0.00140.0416-0.0673-0.16330.0941-0.08590.2964-0.0774-0.06590.34670.16010.2827-16.6112.829441.5138
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A and resid 9:118)
2X-RAY DIFFRACTION2(chain A and resid 119:312)
3X-RAY DIFFRACTION3(chain A and resid 313:354)
4X-RAY DIFFRACTION4chain S
5X-RAY DIFFRACTION5chain B

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