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- PDB-6nbs: WT ERK2 with compound 2507-8 -

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Basic information

Entry
Database: PDB / ID: 6nbs
TitleWT ERK2 with compound 2507-8
ComponentsMitogen-activated protein kinase 1
KeywordsTransferase/Transferase Inhibitor / Inhibitor / MAPK / Transferase-Transferase Inhibitor complex
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 / 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 / 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 / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / FCERI mediated MAPK activation / Regulation of HSF1-mediated heat shock response / MAP2K and MAPK activation / diadenosine tetraphosphate biosynthetic process / Recycling pathway of L1 / neural crest cell development / phospho-PLA2 pathway / Signaling by MAPK mutants / Suppression of apoptosis / RAF-independent MAPK1/3 activation / Signaling by Activin / Gastrin-CREB signalling pathway via PKC and MAPK / caveolin-mediated endocytosis / cardiac neural crest cell development involved in heart development / cytosine metabolic process / response to epidermal growth factor / ERKs are inactivated / mitogen-activated protein kinase kinase kinase binding / Signaling by MAP2K mutants / Signaling by NODAL / RSK activation / Golgi Cisternae Pericentriolar Stack Reorganization / positive regulation of macrophage proliferation / Regulation of the apoptosome activity / regulation of cellular pH / outer ear morphogenesis / regulation of Golgi inheritance / Thrombin signalling through proteinase activated receptors (PARs) / RAF/MAP kinase cascade / Signaling by LTK in cancer / : / ERBB signaling pathway / labyrinthine layer blood vessel development / mammary gland epithelial cell proliferation / Neutrophil degranulation / trachea formation / Negative feedback regulation of MAPK pathway / regulation of early endosome to late endosome transport / regulation of stress-activated MAPK cascade / IFNG signaling activates MAPKs / Frs2-mediated activation / positive regulation of macrophage chemotaxis / ERBB2-ERBB3 signaling pathway / lung morphogenesis / response to exogenous dsRNA / regulation of cytoskeleton organization / pseudopodium / Activation of the AP-1 family of transcription factors / ERK/MAPK targets / androgen receptor signaling pathway / face development / : / RUNX2 regulates osteoblast differentiation / positive regulation of telomere capping / Recycling pathway of L1 / MAPK1 (ERK2) activation / Bergmann glial cell differentiation / thyroid gland development / negative regulation of cell differentiation / Advanced glycosylation endproduct receptor signaling / decidualization / steroid hormone receptor signaling pathway / Transcriptional and post-translational regulation of MITF-M expression and activity
Similarity search - Function
Mitogen-activated protein (MAP) kinase, ERK1/2 / : / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / 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. ...Mitogen-activated protein (MAP) kinase, ERK1/2 / : / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / 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
Similarity search - Domain/homology
Chem-KJ4 / (5S)-5-benzyl-4,5-dihydro-1H-imidazol-2-amine / Mitogen-activated protein kinase 1 / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsSammons, R.M. / Perry, N.A. / Cho, E.J. / Kaoud, T.S. / Zamora-Olivares, D.P. / Piserchio, A. / Houghten, R.A. / Giulianotti, M. / Li, Y. / Debevec, G. ...Sammons, R.M. / Perry, N.A. / Cho, E.J. / Kaoud, T.S. / Zamora-Olivares, D.P. / Piserchio, A. / Houghten, R.A. / Giulianotti, M. / Li, Y. / Debevec, G. / Gurevich, V.V. / Ghose, R. / Iverson, T.M. / Dalby, K.N.
Funding support United States, 2items
OrganizationGrant numberCountry
American Heart Association16PRE30180007 United States
American Heart Association18PRE34030017 United States
CitationJournal: Acs Chem.Biol. / Year: 2019
Title: A Novel Class of Common Docking Domain Inhibitors That Prevent ERK2 Activation and Substrate Phosphorylation.
Authors: Sammons, R.M. / Perry, N.A. / Li, Y. / Cho, E.J. / Piserchio, A. / Zamora-Olivares, D.P. / Ghose, R. / Kaoud, T.S. / Debevec, G. / Bartholomeusz, C. / Gurevich, V.V. / Iverson, T.M. / ...Authors: Sammons, R.M. / Perry, N.A. / Li, Y. / Cho, E.J. / Piserchio, A. / Zamora-Olivares, D.P. / Ghose, R. / Kaoud, T.S. / Debevec, G. / Bartholomeusz, C. / Gurevich, V.V. / Iverson, T.M. / Giulianotti, M. / Houghten, R.A. / Dalby, K.N.
History
DepositionDec 10, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 31, 2019Provider: repository / Type: Initial release
Revision 1.1Aug 12, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Sep 8, 2021Group: Database references / Source and taxonomy / Structure summary
Category: database_2 / entity_name_com ...database_2 / entity_name_com / entity_src_gen / struct_ref / struct_ref_seq / struct_ref_seq_dif
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_name_com.name / _entity_src_gen.gene_src_common_name / _entity_src_gen.pdbx_gene_src_gene / _entity_src_gen.pdbx_gene_src_ncbi_taxonomy_id / _entity_src_gen.pdbx_gene_src_scientific_name / _struct_ref.db_code / _struct_ref.pdbx_align_begin / _struct_ref.pdbx_db_accession / _struct_ref.pdbx_seq_one_letter_code / _struct_ref_seq.db_align_beg / _struct_ref_seq.db_align_end / _struct_ref_seq.pdbx_auth_seq_align_beg / _struct_ref_seq.pdbx_db_accession / _struct_ref_seq.seq_align_beg
Revision 1.3Oct 11, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)43,2715
Polymers42,4331
Non-polymers8384
Water3,747208
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: NMR analysis performed on the inhibitor to show assembly
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)48.895, 71.242, 60.167
Angle α, β, γ (deg.)90.00, 109.37, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 42432.777 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, UniProt: P28482*PLUS, mitogen-activated protein kinase

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Non-polymers , 5 types, 212 molecules

#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-KJ7 / (5S)-5-benzyl-4,5-dihydro-1H-imidazol-2-amine


Mass: 175.230 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H13N3
#5: Chemical ChemComp-KJ4 / N-{3-[(2Z,4S)-1-(2-{[2-(2-amino-1H-imidazol-1-yl)ethyl](methyl)amino}ethyl)-3-(3-cyclohexylpropyl)-2-iminoimidazolidin-4-yl]propyl}guanidine


Mass: 474.689 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H46N10
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 208 / 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: 2.33 Å3/Da / Density % sol: 47.21 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop
Details: 33% PEG 5,000 MME, 0.25 M ammonium sulfate, 0.1 M MES, pH 6.5

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Data collection

DiffractionMean temperature: 446.15 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.9798 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Oct 23, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9798 Å / Relative weight: 1
ReflectionResolution: 1.9→38.72 Å / Num. obs: 30765 / % possible obs: 99.9 % / Redundancy: 4.5 % / Biso Wilson estimate: 22.6 Å2 / Rmerge(I) obs: 0.076 / Rsym value: 0.076 / Net I/σ(I): 35.057
Reflection shellResolution: 1.9→1.93 Å / Redundancy: 4.5 % / Rmerge(I) obs: 0.565 / Mean I/σ(I) obs: 5.015 / CC1/2: 0.607 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX(1.14_3211: ???)refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1ERK

1erk
PDB Unreleased entry


Resolution: 1.9→38.72 Å / SU ML: 0.18 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 22.5
RfactorNum. reflection% reflection
Rfree0.2218 1424 4.64 %
Rwork0.1801 --
obs0.182 30668 99.63 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.9→38.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2791 0 58 208 3057
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072946
X-RAY DIFFRACTIONf_angle_d0.8223993
X-RAY DIFFRACTIONf_dihedral_angle_d4.6112481
X-RAY DIFFRACTIONf_chiral_restr0.054434
X-RAY DIFFRACTIONf_plane_restr0.005510
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9003-1.96820.26271260.20992833X-RAY DIFFRACTION97
1.9682-2.0470.22641490.19942916X-RAY DIFFRACTION100
2.047-2.14020.30341410.19032928X-RAY DIFFRACTION100
2.1402-2.2530.26231400.19152910X-RAY DIFFRACTION100
2.253-2.39410.23171360.18862950X-RAY DIFFRACTION100
2.3941-2.5790.23011510.18252917X-RAY DIFFRACTION100
2.579-2.83840.25031490.19132912X-RAY DIFFRACTION100
2.8384-3.2490.23671360.18222952X-RAY DIFFRACTION100
3.249-4.09260.20251450.16522947X-RAY DIFFRACTION100
4.0926-38.72830.18241510.16972979X-RAY DIFFRACTION100

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