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- PDB-5nhf: Human Erk2 with an Erk1/2 inhibitor -

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Basic information

Entry
Database: PDB / ID: 5nhf
TitleHuman Erk2 with an Erk1/2 inhibitor
ComponentsMitogen-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 / Signaling by MAP2K mutants / Signaling by NODAL / response to epidermal growth factor / RSK activation / Golgi Cisternae Pericentriolar Stack Reorganization / Regulation of the apoptosome activity / positive regulation of macrophage proliferation / regulation of cellular pH / outer ear morphogenesis / Signaling by LTK in cancer / regulation of Golgi inheritance / labyrinthine layer blood vessel development / ERBB signaling pathway / mammary gland epithelial cell proliferation / Negative feedback regulation of MAPK pathway / trachea formation / regulation of early endosome to late endosome transport / regulation of stress-activated MAPK cascade / Frs2-mediated activation / IFNG signaling activates MAPKs / positive regulation of macrophage chemotaxis / ERBB2-ERBB3 signaling pathway / Activation of the AP-1 family of transcription factors / ERK/MAPK targets / regulation of cytoskeleton organization / response to exogenous dsRNA / lung morphogenesis / RUNX2 regulates osteoblast differentiation / face development / positive regulation of telomere maintenance / MAPK1 (ERK2) activation / Recycling pathway of L1 / pseudopodium / Bergmann glial cell differentiation / androgen receptor signaling pathway / thyroid gland development / Advanced glycosylation endproduct receptor signaling / steroid hormone receptor signaling pathway / negative regulation of cell differentiation / RHO GTPases Activate NADPH Oxidases / MAP kinase activity / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / regulation of ossification / Regulation of HSF1-mediated heat shock response / RHO GTPases Activate WASPs and WAVEs / mitogen-activated protein kinase / JUN kinase activity / phosphatase binding / Signal attenuation / progesterone receptor signaling pathway / Transcriptional and post-translational regulation of MITF-M expression and activity / Estrogen-stimulated signaling through PRKCZ / Schwann cell development / Growth hormone receptor signaling / stress-activated MAPK cascade / Nuclear events stimulated by ALK signaling in cancer / NPAS4 regulates expression of target genes / positive regulation of peptidyl-threonine phosphorylation / phosphotyrosine residue binding / myelination / RNA polymerase II CTD heptapeptide repeat kinase activity / ERK1 and ERK2 cascade / NCAM signaling for neurite out-growth / cellular response to amino acid starvation / insulin-like growth factor receptor signaling pathway / lipopolysaccharide-mediated signaling pathway / ESR-mediated signaling / thymus development / Signal transduction by L1 / Regulation of PTEN gene transcription / peptidyl-threonine phosphorylation / FCGR3A-mediated phagocytosis / B cell receptor signaling pathway / response to nicotine / FCERI mediated MAPK activation / long-term synaptic potentiation / Negative regulation of FGFR3 signaling / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling / Downregulation of SMAD2/3:SMAD4 transcriptional activity / Negative regulation of FGFR1 signaling / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / Spry regulation of FGF signaling / positive regulation of cholesterol biosynthetic process / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / regulation of protein stability / Oncogene Induced Senescence / caveola / 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. / : / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 ...Mitogen-activated protein (MAP) kinase, ERK1/2 / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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-8X5 / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.14 Å
AuthorsDebreczeni, J.E. / Ward, R.A. / Bethel, P. / Cook, C. / Davies, E. / Eckersley, K. / Fairley, G. / Feron, L. / Flemington, V. / Graham, M.A. ...Debreczeni, J.E. / Ward, R.A. / Bethel, P. / Cook, C. / Davies, E. / Eckersley, K. / Fairley, G. / Feron, L. / Flemington, V. / Graham, M.A. / Greenwood, R. / Hopcroft, P. / Howard, T.D. / Hudson, J. / James, M. / Jones, C.D. / Jones, C.R. / Lamont, S. / Lewis, R. / Lindsay, N. / Roberts, K. / Simpson, I. / StGallay, S. / Swallow, S. / Tonge, M.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Structure-Guided Discovery of Potent and Selective Inhibitors of ERK1/2 from a Modestly Active and Promiscuous Chemical Start Point.
Authors: Ward, R.A. / Bethel, P. / Cook, C. / Davies, E. / Debreczeni, J.E. / Fairley, G. / Feron, L. / Flemington, V. / Graham, M.A. / Greenwood, R. / Griffin, N. / Hanson, L. / Hopcroft, P. / ...Authors: Ward, R.A. / Bethel, P. / Cook, C. / Davies, E. / Debreczeni, J.E. / Fairley, G. / Feron, L. / Flemington, V. / Graham, M.A. / Greenwood, R. / Griffin, N. / Hanson, L. / Hopcroft, P. / Howard, T.D. / Hudson, J. / James, M. / Jones, C.D. / Jones, C.R. / Lamont, S. / Lewis, R. / Lindsay, N. / Roberts, K. / Simpson, I. / St-Gallay, S. / Swallow, S. / Tang, J. / Tonge, M. / Wang, Z. / Zhai, B.
History
DepositionMar 21, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 19, 2017Provider: repository / Type: Initial release
Revision 1.1May 10, 2017Group: Database references
Revision 1.2Oct 16, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature
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)44,4853
Polymers43,9851
Non-polymers5002
Water1,31573
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area180 Å2
ΔGint-12 kcal/mol
Surface area15330 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.019, 70.047, 60.363
Angle α, β, γ (deg.)90.00, 109.31, 90.00
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: 43985.414 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: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-8X5 / 2-[2-(oxan-4-ylamino)pyrimidin-4-yl]-5-(phenylmethyl)-6,7-dihydro-1~{H}-pyrrolo[3,2-c]pyridin-4-one


Mass: 403.477 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H25N5O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 73 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.22 Å3/Da / Density % sol: 44.68 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: 30% PegMME2K, 100mM HEPES pH 7.6, 200mM Ammonium sulfate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.976 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Nov 21, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 2.14→46.26 Å / Num. obs: 20963 / % possible obs: 98.2 % / Redundancy: 3.2 % / Biso Wilson estimate: 46.05 Å2 / Rmerge(I) obs: 0.089 / Rpim(I) all: 0.056 / Net I/av σ(I): 9.5 / Net I/σ(I): 9.5
Reflection shellResolution: 2.14→2.22 Å / Redundancy: 3.1 % / Rmerge(I) obs: 0.792 / Mean I/σ(I) obs: 1.6 / Num. unique obs: 1989 / Rpim(I) all: 0.561 / % possible all: 96.4

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
xia2data reduction
Aimlessdata scaling
PHASERphasing
RefinementResolution: 2.14→44.2 Å / Cor.coef. Fo:Fc: 0.927 / Cor.coef. Fo:Fc free: 0.9 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.281 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.271 / SU Rfree Blow DPI: 0.197 / SU Rfree Cruickshank DPI: 0.202
RfactorNum. reflection% reflectionSelection details
Rfree0.259 1312 6.27 %RANDOM
Rwork0.247 ---
obs0.248 20940 98 %-
Displacement parametersBiso mean: 50.08 Å2
Baniso -1Baniso -2Baniso -3
1-6.4777 Å20 Å21.9325 Å2
2---6.9646 Å20 Å2
3---0.4869 Å2
Refine analyzeLuzzati coordinate error obs: 0.41 Å
Refinement stepCycle: 1 / Resolution: 2.14→44.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2649 0 45 73 2767
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012762HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.223766HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d916SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes62HARMONIC2
X-RAY DIFFRACTIONt_gen_planes398HARMONIC5
X-RAY DIFFRACTIONt_it2762HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.19
X-RAY DIFFRACTIONt_other_torsion20.18
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion368SEMIHARMONIC5
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_contact3424SEMIHARMONIC4
LS refinement shellResolution: 2.14→2.24 Å / Rfactor Rfree error: 0 / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.393 164 6.11 %
Rwork0.429 2520 -
all0.426 2684 -
obs--95.51 %
Refinement TLS params.Method: refined / Origin x: -4.2987 Å / Origin y: 8.5561 Å / Origin z: 47.5282 Å
111213212223313233
T-0.0442 Å2-0.0206 Å20.0514 Å2-0.019 Å20.0278 Å2--0.0051 Å2
L1.2751 °20.5822 °20.6146 °2-1.1326 °20.5371 °2--1.2335 °2
S-0.1151 Å °0.1186 Å °0.1326 Å °-0.177 Å °0.0889 Å °0.0653 Å °-0.0832 Å °0.04 Å °0.0261 Å °
Refinement TLS groupSelection details: { A|* }

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