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- PDB-7auv: The structure of ERK2 in complex with dual inhibitor ASTX029 -

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Basic information

Entry
Database: PDB / ID: 7auv
TitleThe structure of ERK2 in complex with dual inhibitor ASTX029
ComponentsMitogen-activated protein kinase 1
KeywordsSIGNALING PROTEIN / Mitogen activated kinase ATP binding Protein phosphorylation Serine/threonine protein kinase
Function / homology
Function and homology information


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 / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / cytosine metabolic process / ERKs are inactivated ...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 / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / cytosine metabolic process / ERKs are inactivated / response to epidermal growth factor / Signaling by MAP2K mutants / Signaling by NODAL / RSK activation / Golgi Cisternae Pericentriolar Stack Reorganization / regulation of cellular pH / positive regulation of macrophage proliferation / outer ear morphogenesis / Regulation of the apoptosome activity / regulation of Golgi inheritance / ERBB signaling pathway / labyrinthine layer blood vessel development / mammary gland epithelial cell proliferation / trachea formation / Negative feedback regulation of MAPK pathway / regulation of cytoskeleton organization / 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 / lung morphogenesis / ERBB2-ERBB3 signaling pathway / response to exogenous dsRNA / face development / Activation of the AP-1 family of transcription factors / androgen receptor signaling pathway / ERK/MAPK targets / Recycling pathway of L1 / RUNX2 regulates osteoblast differentiation / pseudopodium / progesterone receptor signaling pathway / positive regulation of telomere capping / MAPK1 (ERK2) activation / negative regulation of cell differentiation / Bergmann glial cell differentiation / thyroid gland development / Advanced glycosylation endproduct receptor signaling / steroid hormone mediated signaling pathway / RHO GTPases Activate NADPH Oxidases / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / Regulation of HSF1-mediated heat shock response / regulation of ossification / RHO GTPases Activate WASPs and WAVEs / MAP kinase activity / mitogen-activated protein kinase / phosphatase binding / Signal attenuation / Estrogen-stimulated signaling through PRKCZ / Nuclear events stimulated by ALK signaling in cancer / stress-activated MAPK cascade / Schwann cell development / Growth hormone receptor signaling / lipopolysaccharide-mediated signaling pathway / positive regulation of telomerase activity / ERK1 and ERK2 cascade / cellular response to cadmium ion / cellular response to amino acid starvation / positive regulation of telomere maintenance via telomerase / myelination / NPAS4 regulates expression of target genes / NCAM signaling for neurite out-growth / phosphotyrosine residue binding / RNA polymerase II CTD heptapeptide repeat kinase activity / ESR-mediated signaling / insulin-like growth factor receptor signaling pathway / thymus development / response to nicotine / positive regulation of peptidyl-threonine phosphorylation / Regulation of PTEN gene transcription / Signal transduction by L1 / long-term synaptic potentiation / caveola / Negative regulation of FGFR3 signaling / Downregulation of SMAD2/3:SMAD4 transcriptional activity / FCERI mediated MAPK activation / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling / FCGR3A-mediated phagocytosis / Negative regulation of FGFR1 signaling / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / B cell receptor signaling pathway / Spry regulation of FGF signaling / peptidyl-threonine phosphorylation / Signaling by high-kinase activity BRAF mutants / regulation of protein stability / MAP2K and MAPK activation / Oncogene Induced Senescence / mitotic spindle / Regulation of actin dynamics for phagocytic cup formation
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. / Protein kinase domain profile. ...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-RYW / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.76 Å
AuthorsO'Reilly, M.
CitationJournal: Mol.Cancer Ther. / Year: 2021
Title: ASTX029, a Novel Dual-mechanism ERK Inhibitor, Modulates Both the Phosphorylation and Catalytic Activity of ERK.
Authors: Munck, J.M. / Berdini, V. / Bevan, L. / Brothwood, J.L. / Castro, J. / Courtin, A. / East, C. / Ferraldeschi, R. / Heightman, T.D. / Hindley, C.J. / Kucia-Tran, J. / Lyons, J.F. / Martins, V. ...Authors: Munck, J.M. / Berdini, V. / Bevan, L. / Brothwood, J.L. / Castro, J. / Courtin, A. / East, C. / Ferraldeschi, R. / Heightman, T.D. / Hindley, C.J. / Kucia-Tran, J. / Lyons, J.F. / Martins, V. / Muench, S. / Murray, C.W. / Norton, D. / O'Reilly, M. / Reader, M. / Rees, D.C. / Rich, S.J. / Richardson, C.J. / Shah, A.D. / Stanczuk, L. / Thompson, N.T. / Wilsher, N.E. / Woolford, A.J. / Wallis, N.G.
History
DepositionNov 3, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 6, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 13, 2021Group: Data collection / Database references
Category: citation / citation_author ...citation / citation_author / database_PDB_rev / database_PDB_rev_record / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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)43,5026
Polymers42,5521
Non-polymers9505
Water8,413467
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area690 Å2
ΔGint-32 kcal/mol
Surface area16470 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.001, 71.049, 60.920
Angle α, β, γ (deg.)90.000, 110.500, 90.000
Int Tables number4
Space group name H-MP1211

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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: 42551.922 Da / Num. of mol.: 1 / Mutation: C171CME
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK1, ERK2, PRKM1, PRKM2 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P28482, mitogen-activated protein kinase
#2: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-RYW / (2~{R})-2-[5-[5-chloranyl-2-(oxan-4-ylamino)pyrimidin-4-yl]-3-oxidanylidene-1~{H}-isoindol-2-yl]-~{N}-[(1~{S})-1-(3-fluoranyl-5-methoxy-phenyl)-2-oxidanyl-ethyl]propanamide / ASTX029


Mass: 584.038 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H31ClFN5O5 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 467 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 47.31 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.3
Details: 0.2M (NH4)2SO4 32% MPEG 2000 .02M Mercaptoethanol .1M pH=7.2 HEPES/NaOH

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-X / Wavelength: 1.54178 Å
DetectorType: DECTRIS EIGER R 1M / Detector: PIXEL / Date: May 10, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.76→44.49 Å / Num. obs: 32724 / % possible obs: 84.9 % / Redundancy: 3 % / Biso Wilson estimate: 24.78 Å2 / Rrim(I) all: 0.063 / Net I/σ(I): 12.3
Reflection shellResolution: 1.76→1.77 Å / Num. unique obs: 234 / Rrim(I) all: 0.8 / % possible all: 80.9

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
BUSTER2.11.7refinement
PDB_EXTRACT3.27data extraction
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.76→30.16 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.924 / SU R Cruickshank DPI: 0.208 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.143 / SU Rfree Blow DPI: 0.143 / SU Rfree Cruickshank DPI: 0.137
RfactorNum. reflection% reflectionSelection details
Rfree0.229 1674 5.13 %RANDOM
Rwork0.167 ---
obs0.17 32624 84.7 %-
Displacement parametersBiso max: 112.42 Å2 / Biso mean: 29.57 Å2 / Biso min: 9.29 Å2
Baniso -1Baniso -2Baniso -3
1-0.84 Å20 Å22.6765 Å2
2--0.2334 Å20 Å2
3----1.0733 Å2
Refine analyzeLuzzati coordinate error obs: 0.21 Å
Refinement stepCycle: final / Resolution: 1.76→30.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2838 0 91 467 3396
Biso mean--35.75 39.07 -
Num. residues----347
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1312SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes938HARMONIC16
X-RAY DIFFRACTIONt_it5894HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion380SEMIHARMONIC5
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_contact6865SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d5900HARMONIC20.013
X-RAY DIFFRACTIONt_angle_deg10682HARMONIC21.08
X-RAY DIFFRACTIONt_omega_torsion6.16
X-RAY DIFFRACTIONt_other_torsion16.21
LS refinement shellResolution: 1.76→1.78 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.3055 33 5.05 %
Rwork0.2495 620 -
all0.2521 653 -
obs--79.23 %
Refinement TLS params.Method: refined / Origin x: -2.1033 Å / Origin y: 3.489 Å / Origin z: 38.5734 Å
111213212223313233
T-0.0574 Å20.0053 Å20.0084 Å2--0.079 Å2-0.0249 Å2---0.0359 Å2
L0.708 °2-0.1527 °20.3357 °2-0.7947 °2-0.1823 °2--1.1281 °2
S-0.0606 Å °-0.1 Å °0.1014 Å °0.1277 Å °0.0481 Å °-0.0851 Å °-0.0778 Å °-0.0234 Å °0.0125 Å °
Refinement TLS groupSelection details: { A|11 - A|365 }

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