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- PDB-5hd4: Dissecting Therapeutic Resistance to ERK Inhibition Rat Wild Type... -

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Entry
Database: PDB / ID: 5hd4
TitleDissecting Therapeutic Resistance to ERK Inhibition Rat Wild Type SCH772984 in complex with (3R)-1-(2-oxo-2-{4-[4-(pyrimidin-2-yl)phenyl]piperazin-1-yl}ethyl)-N-[3-(pyridin-4-yl)-2H-indazol-5-yl]pyrrolidine-3-carboxamide
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 / 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 / positive regulation of telomere maintenance via telomerase / cellular response to cadmium ion / 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
Chem-38Z / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.45 Å
AuthorsJha, S. / Morris, E.J. / Hruza, A. / Mansueto, M.S. / Schroeder, G. / Arbanas, J. / McMasters, D. / Restaino, C.R. / Dayananth, R. / Black, S. ...Jha, S. / Morris, E.J. / Hruza, A. / Mansueto, M.S. / Schroeder, G. / Arbanas, J. / McMasters, D. / Restaino, C.R. / Dayananth, R. / Black, S. / Elsen, N.L. / Mannarino, A. / Cooper, A. / Fawell, S. / Zawel, L. / Jayaraman, L. / Samatar, A.A.
CitationJournal: Mol.Cancer Ther. / Year: 2016
Title: Dissecting Therapeutic Resistance to ERK Inhibition.
Authors: Jha, S. / Morris, E.J. / Hruza, A. / Mansueto, M.S. / Schroeder, G.K. / Arbanas, J. / McMasters, D. / Restaino, C.R. / Dayananth, P. / Black, S. / Elsen, N.L. / Mannarino, A. / Cooper, A. / ...Authors: Jha, S. / Morris, E.J. / Hruza, A. / Mansueto, M.S. / Schroeder, G.K. / Arbanas, J. / McMasters, D. / Restaino, C.R. / Dayananth, P. / Black, S. / Elsen, N.L. / Mannarino, A. / Cooper, A. / Fawell, S. / Zawel, L. / Jayaraman, L. / Samatar, A.A.
History
DepositionJan 4, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 24, 2016Provider: repository / Type: Initial release
Revision 1.1Jun 1, 2016Group: Database references
Revision 1.2Sep 27, 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 / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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)43,4578
Polymers42,2311
Non-polymers1,2267
Water4,972276
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1270 Å2
ΔGint-27 kcal/mol
Surface area16420 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.532, 91.406, 63.227
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

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Protein , 1 types, 1 molecules A

#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: 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

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Non-polymers , 5 types, 283 molecules

#2: Chemical ChemComp-38Z / (3R)-1-(2-oxo-2-{4-[4-(pyrimidin-2-yl)phenyl]piperazin-1-yl}ethyl)-N-[3-(pyridin-4-yl)-2H-indazol-5-yl]pyrrolidine-3-carboxamide


Mass: 587.674 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H33N9O2
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL / Polyethylene glycol


Mass: 194.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#5: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 276 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.45 Å3/Da / Density % sol: 49.74 %
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 at 500 MICROMOLAR CONCENTRATION

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1.00001 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Dec 17, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00001 Å / Relative weight: 1
ReflectionResolution: 1.45→23.07 Å / Num. obs: 72235 / % possible obs: 97.8 % / Observed criterion σ(I): 2 / Redundancy: 4.4 % / Biso Wilson estimate: 19.2 Å2 / Rmerge(I) obs: 0.049 / Net I/σ(I): 14.5
Reflection shellResolution: 1.45→1.5 Å / Redundancy: 3.9 % / Rmerge(I) obs: 0.523 / Mean I/σ(I) obs: 2.8 / % possible all: 97.3

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Processing

Software
NameVersionClassification
BUSTER2.11.4refinement
DENZO1.97.7data reduction
SCALEPACK1.97.7data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1ERK

1erk
PDB Unreleased entry


Resolution: 1.45→23.07 Å / Cor.coef. Fo:Fc: 0.9572 / Cor.coef. Fo:Fc free: 0.947 / SU R Cruickshank DPI: 0.066 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.06 / SU Rfree Blow DPI: 0.061 / SU Rfree Cruickshank DPI: 0.061
RfactorNum. reflection% reflectionSelection details
Rfree0.1992 3609 5 %RANDOM
Rwork0.1763 ---
obs0.1775 72235 97.48 %-
Displacement parametersBiso mean: 28.94 Å2
Baniso -1Baniso -2Baniso -3
1--2.9266 Å20 Å20 Å2
2--1.2157 Å20 Å2
3---1.7109 Å2
Refine analyzeLuzzati coordinate error obs: 0.185 Å
Refinement stepCycle: LAST / Resolution: 1.45→23.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5673 0 80 276 6029
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0095856HARMONIC2
X-RAY DIFFRACTIONt_angle_deg110573HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1291SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes76HARMONIC2
X-RAY DIFFRACTIONt_gen_planes884HARMONIC5
X-RAY DIFFRACTIONt_it5856HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.72
X-RAY DIFFRACTIONt_other_torsion15.5
X-RAY DIFFRACTIONt_improper_torsion3HARMONIC0
X-RAY DIFFRACTIONt_chiral_improper_torsion376SEMIHARMONIC5
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_contact6639SEMIHARMONIC4
LS refinement shellResolution: 1.45→1.49 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2246 243 5.02 %
Rwork0.2094 4598 -
all0.2102 4841 -
obs--97.48 %
Refinement TLS params.Method: refined / Origin x: 53.0696 Å / Origin y: 19.1187 Å / Origin z: 18.7471 Å
111213212223313233
T-0.0428 Å20.0086 Å2-0.0016 Å2--0.0403 Å20.0007 Å2---0.0467 Å2
L0.9421 °2-0.3003 °2-0.4769 °2-0.5472 °20.063 °2--0.8498 °2
S0.0462 Å °0.1663 Å °-0.0381 Å °-0.0198 Å °-0.0503 Å °0.0553 Å °-0.0318 Å °-0.0928 Å °0.0042 Å °
Refinement TLS groupSelection details: { A|* }

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