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- PDB-7w5o: Crystal structure of ERK2 with an allosteric inhibitor -

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Basic information

Entry
Database: PDB / ID: 7w5o
TitleCrystal structure of ERK2 with an allosteric inhibitor
ComponentsMitogen-activated protein kinase 1
KeywordsTRANSFERASE / protein kinase / allosteric inhibitor / activation loop
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-5ID / Chem-6GI / MALONIC ACID / SUCCINIC ACID / D(-)-TARTARIC ACID / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.35 Å
AuthorsYoshida, M. / Kinoshita, T.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Biochem.Biophys.Res.Commun. / Year: 2022
Title: Identification of a novel target site for ATP-independent ERK2 inhibitors.
Authors: Yoshida, M. / Nagao, H. / Sugiyama, H. / Sawa, M. / Kinoshita, T.
History
DepositionNov 30, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 23, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)87,00516
Polymers84,6212
Non-polymers2,38414
Water2,144119
1
A: Mitogen-activated protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,5129
Polymers42,3101
Non-polymers1,2028
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area110 Å2
ΔGint-7 kcal/mol
Surface area16700 Å2
MethodPISA
2
B: Mitogen-activated protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,4927
Polymers42,3101
Non-polymers1,1826
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area16030 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.812, 82.812, 274.440
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212
Space group name HallP4abw2nw
Symmetry operation#1: x,y,z
#2: -y+1/2,x+1/2,z+1/4
#3: y+1/2,-x+1/2,z+3/4
#4: x+1/2,-y+1/2,-z+3/4
#5: -x+1/2,y+1/2,-z+1/4
#6: -x,-y,z+1/2
#7: y,x,-z
#8: -y,-x,-z+1/2

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Mitogen-activated protein kinase 1 / MAP kinase 1 / MAPK 1 / ERT1 / Extracellular signal-regulated kinase 2 / ERK-2 / MAP kinase isoform ...MAP kinase 1 / MAPK 1 / ERT1 / Extracellular signal-regulated kinase 2 / ERK-2 / MAP kinase isoform p42 / p42-MAPK / Mitogen-activated protein kinase 2 / MAP kinase 2 / MAPK 2


Mass: 42310.410 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK1, ERK2, PRKM1, PRKM2 / Plasmid: pGEX6p-1 / Production host: Escherichia coli BL21 (bacteria)
References: UniProt: P28482, mitogen-activated protein kinase

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Non-polymers , 8 types, 133 molecules

#2: Chemical ChemComp-5ID / (2R,3R,4S,5R)-2-(4-AMINO-5-IODO-7H-PYRROLO[2,3-D]PYRIMIDIN-7-YL)-5-(HYDROXYMETHYL)TETRAHYDROFURAN-3,4-DIOL / 5-IODOTUBERCIDIN


Mass: 392.150 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H13IN4O4
#3: Chemical
ChemComp-MLA / MALONIC ACID / DICARBOXYLIC ACID C3 / PROPANEDIOLIC ACID / METHANEDICARBOXYLIC ACID


Mass: 104.061 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C3H4O4
#4: Chemical ChemComp-SIN / SUCCINIC ACID


Mass: 118.088 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H6O4
#5: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#6: Chemical ChemComp-EPE / 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / HEPES


Mass: 238.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H18N2O4S / Comment: pH buffer*YM
#7: Chemical ChemComp-TAR / D(-)-TARTARIC ACID


Mass: 150.087 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H6O6
#8: Chemical ChemComp-6GI / 13-[4-({Imidazo[1,2-a]pyridin-2-yl}methoxy)phenyl]-4,8-dioxa-12,14,16,18-tetraazatetracyclo[9.7.0.0^{3,9}.0^{12,17}]octadeca-1(11),2,9,15,17-pentaen-15-amine


Mass: 481.506 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H23N7O3
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 119 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN

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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: 2.78 Å3/Da / Density % sol: 55.74 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7 / Details: Tacsimate, HEPES, PEGMME5000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL44XU / Wavelength: 0.9 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jul 4, 2020
RadiationMonochromator: mirrrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9 Å / Relative weight: 1
ReflectionResolution: 2.35→49.32 Å / Num. obs: 46821 / % possible obs: 99.8 % / Redundancy: 13.2 % / Biso Wilson estimate: 55.87 Å2 / CC1/2: 0.99 / Rmerge(I) obs: 0.179 / Net I/σ(I): 99.9
Reflection shellResolution: 2.35→2.43 Å / Num. unique obs: 40848 / CC1/2: 0.62 / % possible all: 99.43

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
PHENIX1.19.2_4158refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4qp1
Resolution: 2.35→49.32 Å / SU ML: 0.3648 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 31.559
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2788 1749 4.28 %
Rwork0.2254 39091 -
obs0.2276 40840 99.83 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 68.79 Å2
Refinement stepCycle: LAST / Resolution: 2.35→49.32 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5699 0 155 119 5973
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00975990
X-RAY DIFFRACTIONf_angle_d1.08688119
X-RAY DIFFRACTIONf_chiral_restr0.059873
X-RAY DIFFRACTIONf_plane_restr0.00991039
X-RAY DIFFRACTIONf_dihedral_angle_d23.7082259
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.35-2.420.39481400.34613140X-RAY DIFFRACTION99.42
2.42-2.50.36281440.30993205X-RAY DIFFRACTION99.82
2.5-2.590.33241440.2983223X-RAY DIFFRACTION99.85
2.59-2.690.34981420.2833180X-RAY DIFFRACTION99.79
2.69-2.810.32331430.28163198X-RAY DIFFRACTION99.79
2.81-2.960.3741460.27343228X-RAY DIFFRACTION99.73
2.96-3.150.34791420.25913215X-RAY DIFFRACTION99.79
3.15-3.390.271450.24143239X-RAY DIFFRACTION100
3.39-3.730.3141470.2283280X-RAY DIFFRACTION99.94
3.73-4.270.24981470.19473290X-RAY DIFFRACTION100
4.27-5.380.23291500.18993339X-RAY DIFFRACTION99.97
5.38-49.320.24421590.20453554X-RAY DIFFRACTION99.89

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