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- PDB-6slg: HUMAN ERK2 WITH ERK1/2 INHIBITOR, AZD0364. -

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Basic information

Entry
Database: PDB / ID: 6slg
TitleHUMAN ERK2 WITH ERK1/2 INHIBITOR, AZD0364.
Components
  • ERK-tide
  • Mitogen-activated protein kinase 1
KeywordsTRANSFERASE / ERK2 / KINASE / INHIBITOR / ONCOLOGY
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 / ERKs are inactivated / cytosine metabolic process ...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 / ERKs are inactivated / cytosine metabolic process / response to epidermal growth factor / Signaling by MAP2K mutants / Signaling by NODAL / RSK activation / Golgi Cisternae Pericentriolar Stack Reorganization / positive regulation of macrophage proliferation / Regulation of the apoptosome activity / outer ear morphogenesis / regulation of cellular pH / 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 / face development / Activation of the AP-1 family of transcription factors / ERK/MAPK targets / progesterone receptor signaling pathway / androgen receptor signaling pathway / RUNX2 regulates osteoblast differentiation / pseudopodium / Recycling pathway of L1 / MAPK1 (ERK2) activation / Bergmann glial cell differentiation / negative regulation of cell differentiation / positive regulation of telomere capping / thyroid gland development / Advanced glycosylation endproduct receptor signaling / steroid hormone receptor signaling pathway / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / RHO GTPases Activate NADPH Oxidases / Regulation of HSF1-mediated heat shock response / MAP kinase activity / regulation of ossification / RHO GTPases Activate WASPs and WAVEs / phosphatase binding / mitogen-activated protein kinase / Signal attenuation / Estrogen-stimulated signaling through PRKCZ / Nuclear events stimulated by ALK signaling in cancer / Schwann cell development / Growth hormone receptor signaling / stress-activated MAPK cascade / lipopolysaccharide-mediated signaling pathway / : / positive regulation of telomere maintenance via telomerase / cellular response to cadmium ion / NPAS4 regulates expression of target genes / ERK1 and ERK2 cascade / myelination / cellular response to amino acid starvation / 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 / Negative regulation of FGFR4 signaling / FCGR3A-mediated phagocytosis / Negative regulation of FGFR1 signaling / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / peptidyl-threonine phosphorylation / B cell receptor signaling pathway / Spry regulation of FGF signaling / Signaling by high-kinase activity BRAF mutants / response to nicotine / 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-LHZ / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.33 Å
AuthorsBreed, J. / Phillips, C.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Discovery of a Potent and Selective Oral Inhibitor of ERK1/2 (AZD0364) That Is Efficacious in Both Monotherapy and Combination Therapy in Models of Nonsmall Cell Lung Cancer (NSCLC).
Authors: Ward, R.A. / Anderton, M.J. / Bethel, P. / Breed, J. / Cook, C. / Davies, E.J. / Dobson, A. / Dong, Z. / Fairley, G. / Farrington, P. / Feron, L. / Flemington, V. / Gibbons, F.D. / Graham, M. ...Authors: Ward, R.A. / Anderton, M.J. / Bethel, P. / Breed, J. / Cook, C. / Davies, E.J. / Dobson, A. / Dong, Z. / Fairley, G. / Farrington, P. / Feron, L. / Flemington, V. / Gibbons, F.D. / Graham, M.A. / Greenwood, R. / Hanson, L. / Hopcroft, P. / Howells, R. / Hudson, J. / James, M. / Jones, C.D. / Jones, C.R. / Li, Y. / Lamont, S. / Lewis, R. / Lindsay, N. / McCabe, J. / McGuire, T. / Rawlins, P. / Roberts, K. / Sandin, L. / Simpson, I. / Swallow, S. / Tang, J. / Tomkinson, G. / Tonge, M. / Wang, Z. / Zhai, B.
History
DepositionAug 19, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 20, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 8, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.2May 15, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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
B: ERK-tide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,3369
Polymers44,4012
Non-polymers9357
Water3,585199
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1550 Å2
ΔGint-20 kcal/mol
Surface area15630 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.720, 70.510, 60.420
Angle α, β, γ (deg.)90.000, 109.910, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Protein / Protein/peptide , 2 types, 2 molecules AB

#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: 43909.297 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 (E. coli)
References: UniProt: P28482, mitogen-activated protein kinase
#2: Protein/peptide ERK-tide


Mass: 491.580 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 (E. coli)

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Non-polymers , 4 types, 206 molecules

#3: Chemical ChemComp-LHZ / (6~{R})-7-[[3,4-bis(fluoranyl)phenyl]methyl]-6-(methoxymethyl)-2-[5-methyl-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-5,6-dihydroimidazo[1,2-a]pyrazin-8-one / AZD0364


Mass: 494.497 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H24F2N8O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-SO4 / SULFATE ION


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


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 199 / 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: 2.2 Å3/Da / Density % sol: 44.03 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: PegMME2K HEPES pH 7.6 ammonium sulfate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.97949 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Dec 5, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 1.28→70.51 Å / Num. obs: 71741 / % possible obs: 73.6 % / Redundancy: 4.3 % / Biso Wilson estimate: 17.73 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.028 / Rpim(I) all: 0.014 / Rrim(I) all: 0.031 / Net I/σ(I): 24.5 / Num. measured all: 308365
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.28-1.351.40.707216915460.5450.6580.9690.911
4.06-70.5150.0231577531600.9990.0120.02665.299.6

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
Aimless0.5.21data scaling
PDB_EXTRACT3.25data extraction
XDSdata reduction
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.33→26.35 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.941 / SU R Cruickshank DPI: 0.066 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.066 / SU Rfree Blow DPI: 0.066 / SU Rfree Cruickshank DPI: 0.066
RfactorNum. reflection% reflectionSelection details
Rfree0.228 3469 4.91 %RANDOM
Rwork0.206 ---
obs0.207 70682 79.7 %-
Displacement parametersBiso max: 86.35 Å2 / Biso mean: 23.18 Å2 / Biso min: 9.42 Å2
Baniso -1Baniso -2Baniso -3
1--0.214 Å20 Å2-0.3673 Å2
2--0.2511 Å20 Å2
3----0.0371 Å2
Refine analyzeLuzzati coordinate error obs: 0.19 Å
Refinement stepCycle: final / Resolution: 1.33→26.35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2644 0 62 199 2905
Biso mean--27.45 27.37 -
Num. residues----337
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d942SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes501HARMONIC5
X-RAY DIFFRACTIONt_it2801HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion371SEMIHARMONIC5
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_contact3545SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2801HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3812HARMONIC21.04
X-RAY DIFFRACTIONt_omega_torsion3.53
X-RAY DIFFRACTIONt_other_torsion15.31
LS refinement shellResolution: 1.33→1.37 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2433 71 5.02 %
Rwork0.2397 1343 -
all0.2399 1414 -
obs--16.85 %
Refinement TLS params.Method: refined / Origin x: 5.2612 Å / Origin y: -0.0478 Å / Origin z: 18.7301 Å
111213212223313233
T-0.0287 Å2-0.0029 Å2-0.0033 Å2--0.0317 Å20.0105 Å2---0.0301 Å2
L0.6785 °20.3065 °20.3296 °2-0.5946 °20.2249 °2--0.6828 °2
S-0.0684 Å °0.0907 Å °0.0681 Å °-0.0921 Å °0.036 Å °0.0553 Å °-0.054 Å °0.0349 Å °0.0324 Å °
Refinement TLS groupSelection details: { A|* }

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