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- PDB-8aoj: Specific covalent inhibitor of ERK2 -

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Basic information

Entry
Database: PDB / ID: 8aoj
TitleSpecific covalent inhibitor of ERK2
ComponentsMitogen-activated protein kinase 1
KeywordsSIGNALING PROTEIN / serine-threonine kinase / transcriptional repressor / cell cycle / ATP binding
Function / homology
Function and homology information


phospho-PLA2 pathway / Signaling by MAPK mutants / RAF-independent MAPK1/3 activation / Suppression of apoptosis / 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 / RAF-independent MAPK1/3 activation / Suppression of apoptosis / 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 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 / regulation of cytoskeleton organization / Activation of the AP-1 family of transcription factors / face development / ERK/MAPK targets / androgen receptor signaling pathway / pseudopodium / RUNX2 regulates osteoblast differentiation / Recycling pathway of L1 / progesterone receptor signaling pathway / MAPK1 (ERK2) activation / negative regulation of cell differentiation / Bergmann glial cell differentiation / positive regulation of telomere capping / 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 / MAP kinase activity / regulation of ossification / RHO GTPases Activate WASPs and WAVEs / mitogen-activated protein kinase / phosphatase binding / Nuclear events stimulated by ALK signaling in cancer / Signal attenuation / Estrogen-stimulated signaling through PRKCZ / Schwann cell development / stress-activated MAPK cascade / Growth hormone receptor signaling / lipopolysaccharide-mediated signaling pathway / positive regulation of telomerase activity / positive regulation of telomere maintenance via telomerase / cellular response to cadmium ion / ERK1 and ERK2 cascade / NPAS4 regulates expression of target genes / cellular response to amino acid starvation / myelination / 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 / positive regulation of peptidyl-threonine phosphorylation / Regulation of PTEN gene transcription / Signal transduction by L1 / caveola / long-term synaptic potentiation / Negative regulation of FGFR3 signaling / Downregulation of SMAD2/3:SMAD4 transcriptional activity / FCERI mediated MAPK activation / Negative regulation of FGFR2 signaling / FCGR3A-mediated phagocytosis / Negative regulation of FGFR4 signaling / Negative regulation of FGFR1 signaling / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / B cell receptor signaling pathway / peptidyl-threonine phosphorylation / Spry regulation of FGF signaling / response to nicotine / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / regulation of protein stability / 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-N8L / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.12 Å
AuthorsCleasby, A.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Not funded United Kingdom
CitationJournal: J.Med.Chem. / Year: 2022
Title: X-ray Screening of an Electrophilic Fragment Library and Application toward the Development of a Novel ERK 1/2 Covalent Inhibitor.
Authors: St Denis, J.D. / Chessari, G. / Cleasby, A. / Cons, B.D. / Cowan, S. / Dalton, S.E. / East, C. / Murray, C.W. / O'Reilly, M. / Peakman, T. / Rapti, M. / Stow, J.L.
History
DepositionAug 8, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 28, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 5, 2022Group: Database references / Category: citation / citation_author
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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)43,2938
Polymers42,5521
Non-polymers7417
Water8,791488
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1080 Å2
ΔGint-21 kcal/mol
Surface area16270 Å2
Unit cell
Length a, b, c (Å)48.687, 70.306, 60.921
Angle α, β, γ (deg.)90.000, 109.800, 90.000
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 / 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
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

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Non-polymers , 5 types, 495 molecules

#2: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#4: 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
#5: Chemical ChemComp-N8L / 1-[(2~{S})-2-(5-methyl-3-pyridin-4-yl-1~{H}-pyrazol-4-yl)pyrrolidin-1-yl]propan-1-one


Mass: 284.356 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H20N4O / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 488 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.31 Å3/Da / Density % sol: 46.65 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.2
Details: 0.2M (NH4)2SO4 33% MPEG 2000 0.02M Mercaptoethanol 0.1M pH=7.2 HEPES/NaOH

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.99987 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jan 30, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99987 Å / Relative weight: 1
ReflectionResolution: 1.12→45.81 Å / Num. obs: 105660 / % possible obs: 92 % / Redundancy: 3.2 % / Rrim(I) all: 0.048 / Net I/σ(I): 13.5
Reflection shellResolution: 1.12→1.237 Å / Mean I/σ(I) obs: 1.7 / Num. unique obs: 5193 / Rrim(I) all: 0.639

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (16-JUL-2021)refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
Aimlessdata scaling
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.12→45.81 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.959 / SU R Cruickshank DPI: 0.046 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.045 / SU Rfree Blow DPI: 0.047 / SU Rfree Cruickshank DPI: 0.045
Details: HYDROGENS WERE FULLY REFINED U VALUES : WITH TLS ADDED WITH FULL OCCUPANCY AT NUCLEAR POSITION. REFINEMENT NOTES. NUMBER OF REFINEMENT NOTES : 1 NOTE 1 : IDEAL-DIST CONTACT TERM CONTACT ...Details: HYDROGENS WERE FULLY REFINED U VALUES : WITH TLS ADDED WITH FULL OCCUPANCY AT NUCLEAR POSITION. REFINEMENT NOTES. NUMBER OF REFINEMENT NOTES : 1 NOTE 1 : IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.2027 5405 5.12 %RANDOM
Rwork0.1791 ---
obs0.1803 105660 70.8 %-
Displacement parametersBiso max: 93.25 Å2 / Biso mean: 22.533 Å2 / Biso min: 9.4 Å2
Baniso -1Baniso -2Baniso -3
1--1.7315 Å20 Å20.4692 Å2
2--0.7211 Å20 Å2
3---1.0104 Å2
Refine analyzeLuzzati coordinate error obs: 0.15 Å
Refinement stepCycle: final / Resolution: 1.12→45.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2778 0 66 488 3332
Biso mean--27.2 35.76 -
Num. residues----340
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1312SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes2HARMONIC2
X-RAY DIFFRACTIONt_gen_planes927HARMONIC16
X-RAY DIFFRACTIONt_it5832HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion382SEMIHARMONIC5
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_contact5554SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d5838HARMONIC20.016
X-RAY DIFFRACTIONt_angle_deg10590HARMONIC21.29
X-RAY DIFFRACTIONt_omega_torsion5.72
X-RAY DIFFRACTIONt_other_torsion14.9
LS refinement shellResolution: 1.12→1.19 Å / Rfactor Rfree error: 0 / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.308 92 4.35 %
Rwork0.287 2022 -
all0.2879 2114 -
obs--8.44 %
Refinement TLS params.Method: refined / Origin x: -1.5488 Å / Origin y: 5.442 Å / Origin z: 38.0563 Å
111213212223313233
T-0.0273 Å2-0.0011 Å20.0087 Å2--0.0044 Å2-0.0015 Å2--0.0171 Å2
L0.3085 °2-0.0936 °20.1071 °2-0 °2-0.0695 °2--0.3463 °2
S-0.016 Å °-0.0242 Å °0.0389 Å °0.0081 Å °0.0262 Å °-0.0061 Å °-0.0028 Å °-0.0126 Å °-0.0102 Å °
Refinement TLS groupSelection details: { A|10 - A|356 }

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