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- PDB-6cpw: Discovery of 3(S)-thiomethyl pyrrolidine ERK inhibitors for oncology -

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Basic information

Entry
Database: PDB / ID: 6cpw
TitleDiscovery of 3(S)-thiomethyl pyrrolidine ERK inhibitors for oncology
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 / ESR-mediated signaling / Regulation of the apoptosome activity / Interferon gamma signaling / Signal transduction by L1 / Negative regulation of FGFR2 signaling / RHO GTPases Activate NADPH Oxidases / Negative regulation of MAPK pathway / 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 / mammary gland epithelial cell proliferation / Neutrophil degranulation / trachea formation / regulation of cytoskeleton organization / regulation of early endosome to late endosome transport / cellular response to organic substance / regulation of stress-activated MAPK cascade / positive regulation of macrophage chemotaxis / response to exogenous dsRNA / lung morphogenesis / ERBB2-ERBB3 signaling pathway / face development / androgen receptor signaling pathway / pseudopodium / progesterone receptor signaling pathway / positive regulation of telomere capping / negative regulation of cell differentiation / Bergmann glial cell differentiation / thyroid gland development / decidualization / steroid hormone mediated signaling pathway / regulation of ossification / MAP kinase activity / phosphatase binding / mitogen-activated protein kinase / stress-activated MAPK cascade / Schwann cell development / sensory perception of pain / lipopolysaccharide-mediated signaling pathway / positive regulation of cardiac muscle cell proliferation / ERK1 and ERK2 cascade / cellular response to cadmium ion / positive regulation of telomere maintenance via telomerase / 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 / positive regulation of translation / thymus development / positive regulation of peptidyl-threonine phosphorylation / response to nicotine / long-term synaptic potentiation
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-F8V / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.85 Å
AuthorsHruza, A. / Hruza, A.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2018
Title: Discovery of 3(S)-thiomethyl pyrrolidine ERK inhibitors for oncology.
Authors: Boga, S.B. / Alhassan, A.B. / Cooper, A.B. / Doll, R. / Shih, N.Y. / Shipps, G. / Deng, Y. / Zhu, H. / Nan, Y. / Sun, R. / Zhu, L. / Desai, J. / Patel, M. / Muppalla, K. / Gao, X. / Wang, J. ...Authors: Boga, S.B. / Alhassan, A.B. / Cooper, A.B. / Doll, R. / Shih, N.Y. / Shipps, G. / Deng, Y. / Zhu, H. / Nan, Y. / Sun, R. / Zhu, L. / Desai, J. / Patel, M. / Muppalla, K. / Gao, X. / Wang, J. / Yao, X. / Kelly, J. / Gudipati, S. / Paliwal, S. / Tsui, H.C. / Wang, T. / Sherborne, B. / Xiao, L. / Hruza, A. / Buevich, A. / Zhang, L.K. / Hesk, D. / Samatar, A.A. / Carr, D. / Long, B. / Black, S. / Dayananth, P. / Windsor, W. / Kirschmeier, P. / Bishop, R.
History
DepositionMar 14, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 23, 2018Provider: repository / Type: Initial release
Revision 1.1May 30, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Oct 4, 2023Group: 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)43,2054
Polymers42,3621
Non-polymers8433
Water4,630257
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)71.341, 91.318, 63.289
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 / 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: 42361.703 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 BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: P63086, mitogen-activated protein kinase
#2: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-F8V / (3S)-N-[3-(4-fluorophenyl)-1H-indazol-5-yl]-3-(methylsulfanyl)-1-(2-oxo-2-{4-[4-(pyrimidin-2-yl)phenyl]piperazin-1-yl}ethyl)pyrrolidine-3-carboxamide


Mass: 650.768 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C35H35FN8O2S
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 257 / 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: 2.43 Å3/Da / Density % sol: 49.45 %
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. 13 DAY SOAK WITH NEW COMPOUND AT 500 MICROMOLAR CONCENTRATION

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Data collection

DiffractionMean temperature: 95 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.54178 Å
DetectorType: RIGAKU RAXIS HTC / Detector: IMAGE PLATE / Date: Sep 6, 2006 / Details: OSMIC
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.85→33.22 Å / Num. obs: 35845 / % possible obs: 99.5 % / Redundancy: 4.7 % / Biso Wilson estimate: 25.41 Å2 / Rmerge(I) obs: 0.88 / Χ2: 1.001 / Net I/σ(I): 14
Reflection shellResolution: 1.85→1.9 Å / Redundancy: 4.6 % / Rmerge(I) obs: 0.492 / Mean I/σ(I) obs: 2.9 / Num. unique obs: 3556 / Χ2: 1.001 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
DENZOdata reduction
SCALEPACKdata scaling
CNXphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 1ERK

1erk
PDB Unreleased entry


Resolution: 1.85→33.22 Å / Cor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.919 / SU R Cruickshank DPI: 0.167 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.13 / SU Rfree Blow DPI: 0.123 / SU Rfree Cruickshank DPI: 0.12
RfactorNum. reflection% reflectionSelection details
Rfree0.224 1803 5.03 %RANDOM
Rwork0.188 ---
obs0.19 35845 99.5 %-
Displacement parametersBiso mean: 31.4 Å2
Baniso -1Baniso -2Baniso -3
1--5.2285 Å20 Å20 Å2
2--2.2759 Å20 Å2
3---2.9527 Å2
Refine analyzeLuzzati coordinate error obs: 0.21 Å
Refinement stepCycle: 1 / Resolution: 1.85→33.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2684 0 57 257 2998
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.015527HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.019987HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1222SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes70HARMONIC2
X-RAY DIFFRACTIONt_gen_planes836HARMONIC5
X-RAY DIFFRACTIONt_it5527HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.43
X-RAY DIFFRACTIONt_other_torsion14.72
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion359SEMIHARMONIC5
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_contact6137SEMIHARMONIC4
LS refinement shellResolution: 1.85→1.9 Å / Total num. of bins used: 18
RfactorNum. reflection% reflection
Rfree0.2385 149 5.23 %
Rwork0.1989 2702 -
all0.2009 2851 -
obs--97.26 %
Refinement TLS params.Method: refined / Origin x: 53.0927 Å / Origin y: 19.1996 Å / Origin z: 19.9867 Å
111213212223313233
T-0.0756 Å20.0113 Å2-0.0042 Å2--0.0522 Å2-0.0051 Å2---0.0753 Å2
L1.2754 °2-0.4259 °2-0.5477 °2-0.5999 °20.1204 °2--0.907 °2
S0.0514 Å °0.1984 Å °-0.0757 Å °-0.0227 Å °-0.0686 Å °0.0788 Å °-0.0479 Å °-0.0816 Å °0.0172 Å °
Refinement TLS groupSelection details: { A|* }

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