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- PDB-4zzo: Human ERK2 in complex with an irreversible inhibitor -

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Basic information

Entry
Database: PDB / ID: 4zzo
TitleHuman ERK2 in complex with an irreversible inhibitor
ComponentsMITOGEN-ACTIVATED PROTEIN KINASE 1
KeywordsTRANSFERASE
Function / homology
Function and homology information


phospho-PLA2 pathway / Signaling by MAPK mutants / RAF-independent MAPK1/3 activation / Suppression of apoptosis / Gastrin-CREB signalling pathway via PKC and MAPK / Signaling by Activin / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / cytosine metabolic process / Signaling by MAP2K mutants ...phospho-PLA2 pathway / Signaling by MAPK mutants / RAF-independent MAPK1/3 activation / Suppression of apoptosis / Gastrin-CREB signalling pathway via PKC and MAPK / Signaling by Activin / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / cytosine metabolic process / Signaling by MAP2K mutants / Signaling by NODAL / ERKs are inactivated / 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 / trachea formation / Negative feedback regulation of MAPK pathway / positive regulation of peptidyl-threonine phosphorylation / regulation of early endosome to late endosome transport / regulation of stress-activated MAPK cascade / IFNG signaling activates MAPKs / Frs2-mediated activation / ERBB2-ERBB3 signaling pathway / MAPK1 (ERK2) activation / positive regulation of macrophage chemotaxis / Activation of the AP-1 family of transcription factors / regulation of cytoskeleton organization / ERK/MAPK targets / RUNX2 regulates osteoblast differentiation / response to exogenous dsRNA / face development / lung morphogenesis / positive regulation of telomere maintenance / Recycling pathway of L1 / pseudopodium / Bergmann glial cell differentiation / androgen receptor signaling pathway / thyroid gland development / steroid hormone receptor signaling pathway / Advanced glycosylation endproduct receptor signaling / RHO GTPases Activate NADPH Oxidases / MAP kinase activity / negative regulation of cell differentiation / regulation of ossification / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / Regulation of HSF1-mediated heat shock response / RHO GTPases Activate WASPs and WAVEs / JUN kinase activity / mitogen-activated protein kinase / Signal attenuation / Estrogen-stimulated signaling through PRKCZ / phosphatase binding / Schwann cell development / Growth hormone receptor signaling / progesterone receptor signaling pathway / stress-activated MAPK cascade / Nuclear events stimulated by ALK signaling in cancer / NPAS4 regulates expression of target genes / phosphotyrosine residue binding / myelination / RNA polymerase II CTD heptapeptide repeat kinase activity / peptidyl-threonine phosphorylation / Transcriptional and post-translational regulation of MITF-M expression and activity / NCAM signaling for neurite out-growth / ERK1 and ERK2 cascade / cellular response to amino acid starvation / insulin-like growth factor receptor signaling pathway / lipopolysaccharide-mediated signaling pathway / ESR-mediated signaling / thymus development / Regulation of PTEN gene transcription / Signal transduction by L1 / B cell receptor signaling pathway / FCGR3A-mediated phagocytosis / FCERI mediated MAPK activation / response to nicotine / 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 / positive regulation of cholesterol biosynthetic process / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / Spry regulation of FGF signaling / 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 / long-term synaptic potentiation
Similarity search - Function
Mitogen-activated protein (MAP) kinase, ERK1/2 / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. ...Mitogen-activated protein (MAP) kinase, ERK1/2 / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-CQ3 / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.63 Å
AuthorsWard, R.A. / Colclough, N. / Challinor, M. / Debreczeni, J.E. / Eckersley, K. / Fairley, G. / Feron, L. / Flemington, V. / Graham, M.A. / Greenwood, R. ...Ward, R.A. / Colclough, N. / Challinor, M. / Debreczeni, J.E. / Eckersley, K. / Fairley, G. / Feron, L. / Flemington, V. / Graham, M.A. / Greenwood, R. / Hopcroft, P. / Howard, T.D. / James, M. / Jones, C.D. / Jones, C.R. / Renshaw, J. / Roberts, K. / Snow, L. / Tonge, M. / Yeung, K.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Structure-Guided Design of Highly Selective and Potent Covalent Inhibitors of Erk1/2.
Authors: Ward, R.A. / Colclough, N. / Challinor, M. / Debreczeni, J. / Eckersley, K. / Fairley, G. / Feron, L. / Flemington, V. / Graham, M.A. / Greenwood, R. / Hopcroft, P. / Howard, T.D. / James, M. ...Authors: Ward, R.A. / Colclough, N. / Challinor, M. / Debreczeni, J. / Eckersley, K. / Fairley, G. / Feron, L. / Flemington, V. / Graham, M.A. / Greenwood, R. / Hopcroft, P. / Howard, T.D. / James, M. / Jones, C.D. / Jones, C.R. / Renshaw, J. / Roberts, K. / Snow, L. / Tonge, M. / Yeung, K.
History
DepositionApr 10, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 27, 2015Provider: repository / Type: Initial release
Revision 1.1Aug 26, 2015Group: Database references
Revision 1.2Nov 6, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_entry_details / pdbx_modification_feature / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_conn.pdbx_leaving_atom_flag / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)41,2643
Polymers40,7921
Non-polymers4722
Water4,035224
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)48.750, 70.070, 60.100
Angle α, β, γ (deg.)90.00, 109.25, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#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: 40791.961 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, RESIDUES 11-360
Source method: isolated from a genetically manipulated source
Details: MODIFIED CYS 161 A / Source: (gene. exp.) HOMO SAPIENS (human) / 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-CQ3 / N-[2-[[5-chloranyl-2-(oxan-4-ylamino)pyrimidin-4-yl]amino]phenyl]propanamide


Mass: 375.853 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H22ClN5O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 224 / 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: 2.38 Å3/Da / Density % sol: 48.32 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.979
DetectorType: DECTRIS PILATUS / Detector: PIXEL / Date: Feb 17, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.63→38.47 Å / Num. obs: 47270 / % possible obs: 99.3 % / Observed criterion σ(I): 2 / Redundancy: 3.3 % / Biso Wilson estimate: 23.15 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 9.9
Reflection shellResolution: 1.63→1.67 Å / Redundancy: 3.2 % / Rmerge(I) obs: 0.57 / Mean I/σ(I) obs: 2.1 / % possible all: 98.8

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NONE

Resolution: 1.63→38.47 Å / Cor.coef. Fo:Fc: 0.9477 / Cor.coef. Fo:Fc free: 0.9327 / SU R Cruickshank DPI: 0.087 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.088 / SU Rfree Blow DPI: 0.097 / SU Rfree Cruickshank DPI: 0.097
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.2373 10093 21.36 %RANDOM
Rwork0.1846 ---
obs0.1913 47250 99.16 %-
Displacement parametersBiso mean: 25.58 Å2
Baniso -1Baniso -2Baniso -3
1--0.5724 Å20 Å21.9502 Å2
2--1.1772 Å20 Å2
3----0.6048 Å2
Refine analyzeLuzzati coordinate error obs: 0.221 Å
Refinement stepCycle: LAST / Resolution: 1.63→38.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2715 0 31 224 2970
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012817HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.013826HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d966SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes65HARMONIC2
X-RAY DIFFRACTIONt_gen_planes419HARMONIC5
X-RAY DIFFRACTIONt_it2817HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.26
X-RAY DIFFRACTIONt_other_torsion17.45
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_contact3549SEMIHARMONIC4
LS refinement shellResolution: 1.63→1.67 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3278 650 18.72 %
Rwork0.2846 2823 -
all0.2925 3473 -
obs--98.71 %
Refinement TLS params.Method: refined / Origin x: -4.5399 Å / Origin y: 8.7209 Å / Origin z: 47.4874 Å
111213212223313233
T-0.1336 Å20.0095 Å20.009 Å2--0.0836 Å20.0057 Å2---0.0977 Å2
L0.5015 °20.1436 °20.2026 °2-0.3219 °20.0546 °2--0.9368 °2
S-0.0191 Å °0.0539 Å °0.0485 Å °-0.0248 Å °0.0254 Å °0.0016 Å °-0.0289 Å °-0.0019 Å °-0.0063 Å °
Refinement TLS groupSelection details: { A|* }

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