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- PDB-4qyy: Discovery of Novel, Dual Mechanism ERK Inhibitors by Affinity Sel... -

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Entry
Database: PDB / ID: 4qyy
TitleDiscovery of Novel, Dual Mechanism ERK Inhibitors by Affinity Selection Screening of an Inactive Kinase State
ComponentsMitogen-activated protein kinase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / TRANSFERASE / SERINE/THREONINE-PROTEIN KINASE / MAP KINASE / 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 / Transcriptional and post-translational regulation of MITF-M expression and activity ...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 / 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 / Estrogen-stimulated signaling through PRKCZ / Regulation of actin dynamics for phagocytic cup formation / 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 / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Interferon gamma 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 / response to alcohol / cellular response to toxic substance / cellular response to methionine / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / mitogen-activated protein kinase kinase kinase binding / cytosine metabolic process / response to epidermal growth factor / positive regulation of macrophage proliferation / outer ear morphogenesis / RAF/MAP kinase cascade / regulation of cellular pH / Thrombin signalling through proteinase activated receptors (PARs) / 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 / cellular response to insulin-like growth factor stimulus / positive regulation of macrophage chemotaxis / ERBB2-ERBB3 signaling pathway / lung morphogenesis / response to exogenous dsRNA / regulation of cytoskeleton organization / face development / androgen receptor signaling pathway / cellular response to platelet-derived growth factor stimulus / pseudopodium / response to testosterone / positive regulation of telomere capping / Bergmann glial cell differentiation / thyroid gland development / negative regulation of cell differentiation / decidualization / steroid hormone receptor signaling pathway / MAP kinase activity / regulation of ossification / estrous cycle / mitogen-activated protein kinase / phosphatase binding / progesterone receptor signaling pathway / Schwann cell development / positive regulation of cardiac muscle cell proliferation / lipopolysaccharide-mediated signaling pathway / stress-activated MAPK cascade / cellular response to cAMP / positive regulation of telomere maintenance via telomerase / sensory perception of pain / cellular response to epidermal growth factor stimulus / phosphotyrosine residue binding / cellular response to cadmium ion / myelination / ERK1 and ERK2 cascade / dendrite cytoplasm
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. ...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
Chem-3G7 / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.65 Å
AuthorsDeng, Y. / Shipps, G.W. / Cooper, A. / English, J.M. / Annis, D.A. / Carr, D. / Nan, Y. / Wang, T. / Zhu, Y.H. / Chuang, C. ...Deng, Y. / Shipps, G.W. / Cooper, A. / English, J.M. / Annis, D.A. / Carr, D. / Nan, Y. / Wang, T. / Zhu, Y.H. / Chuang, C. / Dayananth, P. / Hruza, A.W. / Xiao, L. / Jin, W. / Kirschmeier, P. / Windsor, W.T. / Samatar, A.A.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Discovery of Novel, Dual Mechanism ERK Inhibitors by Affinity Selection Screening of an Inactive Kinase.
Authors: Deng, Y. / Shipps, G.W. / Cooper, A. / English, J.M. / Annis, D.A. / Carr, D. / Nan, Y. / Wang, T. / Zhu, H.Y. / Chuang, C.C. / Dayananth, P. / Hruza, A.W. / Xiao, L. / Jin, W. / ...Authors: Deng, Y. / Shipps, G.W. / Cooper, A. / English, J.M. / Annis, D.A. / Carr, D. / Nan, Y. / Wang, T. / Zhu, H.Y. / Chuang, C.C. / Dayananth, P. / Hruza, A.W. / Xiao, L. / Jin, W. / Kirschmeier, P. / Windsor, W.T. / Samatar, A.A.
History
DepositionJul 26, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 12, 2014Provider: repository / Type: Initial release
Revision 1.1Dec 17, 2014Group: Database references
Revision 1.2Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)43,0045
Polymers42,2311
Non-polymers7734
Water3,387188
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)71.202, 91.409, 63.316
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

#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: 42230.508 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) / Strain (production host): BL21 (DE3)
References: UniProt: P63086, mitogen-activated protein kinase
#2: Chemical ChemComp-3G7 / (3R)-1-{2-[4-(4-acetylphenyl)piperazin-1-yl]-2-oxoethyl}-N-(3-chloro-4-hydroxyphenyl)pyrrolidine-3-carboxamide


Mass: 484.975 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H29ClN4O4
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 188 / 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: 2.44 Å3/Da / Density % sol: 49.58 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.4
Details: 0.1M MES, pH 6.4, 2.0M Ammonium Sulfate, 5% PEG 400, 0.5% DMSO, 1% Glyerol, 0.0005M Olomoucine, 10 day soak with new compound, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 95 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Sep 14, 2004 / Details: Osmic
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.65→29.88 Å / Num. all: 50508 / Num. obs: 49215 / % possible obs: 97.6 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 1.7 / Redundancy: 5.9 % / Biso Wilson estimate: 24.19 Å2 / Rsym value: 0.083 / Net I/σ(I): 18.6
Reflection shellResolution: 1.65→1.71 Å / Mean I/σ(I) obs: 1.7 / Num. unique all: 4589 / Rsym value: 0.602 / % possible all: 92.4

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Processing

Software
NameVersionClassification
StructureStudiodata collection
MOLREPphasing
BUSTER2.11.4refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1ERK

1erk
PDB Unreleased entry


Resolution: 1.65→29.88 Å / Cor.coef. Fo:Fc: 0.915 / Cor.coef. Fo:Fc free: 0.9074 / SU R Cruickshank DPI: 0.128 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2593 2464 5.01 %RANDOM
Rwork0.2275 ---
obs0.2291 49215 97.6 %-
Displacement parametersBiso mean: 32.03 Å2
Baniso -1Baniso -2Baniso -3
1--1.7152 Å20 Å20 Å2
2--0.1047 Å20 Å2
3---1.6105 Å2
Refine analyzeLuzzati coordinate error obs: 0.215 Å
Refinement stepCycle: LAST / Resolution: 1.65→29.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2757 0 49 188 2994
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.015667HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0410247HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1262SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes73HARMONIC2
X-RAY DIFFRACTIONt_gen_planes834HARMONIC5
X-RAY DIFFRACTIONt_it5667HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.63
X-RAY DIFFRACTIONt_other_torsion15.17
X-RAY DIFFRACTIONt_improper_torsion3HARMONIC0
X-RAY DIFFRACTIONt_chiral_improper_torsion367SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact6315SEMIHARMONIC4
LS refinement shellResolution: 1.65→1.69 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2741 164 4.85 %
Rwork0.2576 3216 -
all0.2584 3380 -
obs--97.6 %
Refinement TLS params.Method: refined / Origin x: 52.9821 Å / Origin y: 19.0412 Å / Origin z: 19.4617 Å
111213212223313233
T-0.0482 Å20.0106 Å2-0.0041 Å2--0.0769 Å2-0.0019 Å2---0.0711 Å2
L1.2063 °2-0.505 °2-0.4974 °2-0.7987 °20.0852 °2--0.9119 °2
S0.069 Å °0.2118 Å °-0.0808 Å °-0.047 Å °-0.0809 Å °0.1003 Å °-0.0307 Å °-0.0917 Å °0.0119 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|13 - A|353 A|401 - A|404 A|601 - A|788 }A13 - 353
2X-RAY DIFFRACTION1{ A|13 - A|353 A|401 - A|404 A|601 - A|788 }A401 - 505
3X-RAY DIFFRACTION1{ A|13 - A|353 A|401 - A|404 A|601 - A|788 }A601 - 791

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