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- PDB-3eqb: X-ray structure of the human mitogen-activated protein kinase kin... -

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Basic information

Entry
Database: PDB / ID: 3eqb
TitleX-ray structure of the human mitogen-activated protein kinase kinase 1 (MEK1) in a complex with ligand and MgATP
ComponentsDual specificity mitogen-activated protein kinase kinase 1
KeywordsTRANSFERASE / PROTEIN KINASE STRUCTURE / MITOGEN ACTIVATED PROTEIN KINASE KINASE / SIGNAL TRANSDUCTION / LIGAND CO-COMPLEX / TERNARY CO-COMPLEX WITH KINASE / LIGAND AND MGATP / NON-COMPETITIVE PROTEIN KINASE INHIBITOR / Acetylation / ATP-binding / Disease mutation / Kinase / Nucleotide-binding / Phosphoprotein / Serine/threonine-protein kinase / Tyrosine-protein kinase
Function / homology
Function and homology information


epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / placenta blood vessel development / regulation of axon regeneration / mitogen-activated protein kinase kinase / labyrinthine layer development / MAP-kinase scaffold activity / type B pancreatic cell proliferation / cerebellar cortex formation / Signaling by MAP2K mutants ...epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / placenta blood vessel development / regulation of axon regeneration / mitogen-activated protein kinase kinase / labyrinthine layer development / MAP-kinase scaffold activity / type B pancreatic cell proliferation / cerebellar cortex formation / Signaling by MAP2K mutants / regulation of Golgi inheritance / spindle pole body / trachea formation / Negative feedback regulation of MAPK pathway / regulation of early endosome to late endosome transport / positive regulation of axonogenesis / regulation of stress-activated MAPK cascade / Frs2-mediated activation / ERBB2-ERBB3 signaling pathway / protein kinase activator activity / MAPK3 (ERK1) activation / endodermal cell differentiation / face development / MAP kinase kinase activity / Bergmann glial cell differentiation / Uptake and function of anthrax toxins / thyroid gland development / Schwann cell development / keratinocyte differentiation / protein serine/threonine/tyrosine kinase activity / myelination / ERK1 and ERK2 cascade / protein serine/threonine kinase activator activity / MAP3K8 (TPL2)-dependent MAPK1/3 activation / insulin-like growth factor receptor signaling pathway / thymus development / Signal transduction by L1 / cell motility / RAF activation / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / positive regulation of protein serine/threonine kinase activity / neuron differentiation / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / chemotaxis / cellular senescence / Signaling by BRAF and RAF1 fusions / MAPK cascade / late endosome / heart development / scaffold protein binding / protein tyrosine kinase activity / positive regulation of ERK1 and ERK2 cascade / early endosome / protein kinase activity / negative regulation of cell population proliferation / protein serine kinase activity / focal adhesion / protein serine/threonine kinase activity / centrosome / positive regulation of gene expression / positive regulation of DNA-templated transcription / Golgi apparatus / endoplasmic reticulum / signal transduction / mitochondrion / ATP binding / nucleus / plasma membrane / cytosol
Similarity search - Function
: / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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 ...: / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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
ADENOSINE-5'-TRIPHOSPHATE / Chem-LUG / Dual specificity mitogen-activated protein kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.62 Å
AuthorsOhren, J.F. / Pavlovsky, A. / Zhang, E.
Citation
Journal: Bioorg.Med.Chem.Lett. / Year: 2008
Title: 2-Alkylamino- and alkoxy-substituted 2-amino-1,3,4-oxadiazoles-O-Alkyl benzohydroxamate esters replacements retain the desired inhibition and selectivity against MEK (MAP ERK kinase).
Authors: Warmus, J.S. / Flamme, C. / Zhang, L.Y. / Barrett, S. / Bridges, A. / Chen, H. / Gowan, R. / Kaufman, M. / Sebolt-Leopold, J. / Leopold, W. / Merriman, R. / Ohren, J. / Pavlovsky, A. / ...Authors: Warmus, J.S. / Flamme, C. / Zhang, L.Y. / Barrett, S. / Bridges, A. / Chen, H. / Gowan, R. / Kaufman, M. / Sebolt-Leopold, J. / Leopold, W. / Merriman, R. / Ohren, J. / Pavlovsky, A. / Przybranowski, S. / Tecle, H. / Valik, H. / Whitehead, C. / Zhang, E.
#1: Journal: J.Med.Chem. / Year: 2007
Title: 4-anilino-5-carboxamido-2-pyridone derivatives as noncompetitive inhibitors of mitogen-activated protein kinase kinase.
Authors: Spicer, J.A. / Rewcastle, G.W. / Kaufman, M.D. / Black, S.L. / Plummer, M.S. / Denny, W.A. / Quin, J. / Shahripour, A.B. / Barrett, S.D. / Whitehead, C.E. / Milbank, J.B. / Ohren, J.F. / ...Authors: Spicer, J.A. / Rewcastle, G.W. / Kaufman, M.D. / Black, S.L. / Plummer, M.S. / Denny, W.A. / Quin, J. / Shahripour, A.B. / Barrett, S.D. / Whitehead, C.E. / Milbank, J.B. / Ohren, J.F. / Gowan, R.C. / Omer, C. / Camp, H.S. / Esmaeil, N. / Moore, K. / Sebolt-Leopold, J.S. / Pryzbranowski, S. / Merriman, R.L. / Ortwine, D.F. / Warmus, J.S. / Flamme, C.M. / Pavlovsky, A.G. / Tecle, H.
#2: Journal: Nat.Struct.Mol.Biol. / Year: 2004
Title: Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition.
Authors: Ohren, J.F. / Chen, H. / Pavlovsky, A. / Whitehead, C. / Zhang, E. / Kuffa, P. / Yan, C. / McConnell, P. / Spessard, C. / Banotai, C. / Mueller, W.T. / Delaney, A. / Omer, C. / Sebolt- ...Authors: Ohren, J.F. / Chen, H. / Pavlovsky, A. / Whitehead, C. / Zhang, E. / Kuffa, P. / Yan, C. / McConnell, P. / Spessard, C. / Banotai, C. / Mueller, W.T. / Delaney, A. / Omer, C. / Sebolt-Leopold, J. / Dudley, D.T. / Leung, I.K. / Flamme, C. / Warmus, J. / Kaufman, M. / Barrett, S. / Tecle, H. / Hasemann, C.A.
History
DepositionSep 30, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 11, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Sep 6, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _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: Dual specificity mitogen-activated protein kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,8664
Polymers36,8591
Non-polymers1,0073
Water39622
1
A: Dual specificity mitogen-activated protein kinase kinase 1
hetero molecules

A: Dual specificity mitogen-activated protein kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,7328
Polymers73,7192
Non-polymers2,0136
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_655-x+1,-y,z1
Buried area3720 Å2
ΔGint-40 kcal/mol
Surface area26620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.128, 82.128, 129.099
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number171
Space group name H-MP62

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Components

#1: Protein Dual specificity mitogen-activated protein kinase kinase 1 / MAP kinase kinase 1 / MAPKK 1 / ERK activator kinase 1 / MAPK/ERK kinase 1 / MEK1


Mass: 36859.469 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAP2K1, MEK1, PRKMK1 / Production host: Escherichia coli (E. coli)
References: UniProt: Q02750, mitogen-activated protein kinase kinase
#2: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Comment: ATP, energy-carrying molecule*YM
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-LUG / N-(5-{3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}-1,3,4-oxadiazol-2-yl)ethane-1,2-diamine


Mass: 475.207 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H13F3IN5O
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 22 / Source method: isolated from a natural source / Formula: H2O

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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: 3.41 Å3/Da / Density % sol: 63.93 %

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Sep 13, 2001
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.6→71.07 Å / Num. obs: 14284 / % possible obs: 96.7 % / Redundancy: 5.6 % / Rsym value: 0.123

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Processing

Software
NameClassification
HKL-2000data collection
REFMACrefinement
DENZOdata reduction
SCALEPACKdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: pdb entry 1S9J

1s9j


Resolution: 2.62→20 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.925 / SU B: 11.301 / SU ML: 0.235 / Cross valid method: THROUGHOUT / ESU R: 0.425 / ESU R Free: 0.297 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.26394 725 5.1 %RANDOM
Rwork0.20952 ---
obs0.21218 13554 95.88 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 68.441 Å2
Baniso -1Baniso -2Baniso -3
1-2.4 Å21.2 Å20 Å2
2--2.4 Å20 Å2
3----3.6 Å2
Refinement stepCycle: LAST / Resolution: 2.62→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2267 0 58 22 2347
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0222375
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.42.0123210
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5715288
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.31824.4998
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.5315427
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.9141512
X-RAY DIFFRACTIONr_chiral_restr0.0790.2349
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0211749
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.7031.51439
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.32422324
X-RAY DIFFRACTIONr_scbond_it1.4543936
X-RAY DIFFRACTIONr_scangle_it2.5534.5885
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.62→2.687 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.421 45 -
Rwork0.317 915 -
obs--87.27 %

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