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- PDB-3orn: Mitogen-activated protein kinase kinase 1 (MEK1) in complex with ... -

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Basic information

Entry
Database: PDB / ID: 3orn
TitleMitogen-activated protein kinase kinase 1 (MEK1) in complex with CH4987655 and MgAMP-PNP
ComponentsDual specificity mitogen-activated protein kinase kinase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase / kinase inhibitor / allosteric / mitogen-activated protein kinase kinase / TRANSFERASE-TRANSFERASE INHIBITOR complex
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 / type B pancreatic cell proliferation / labyrinthine layer development / MAP-kinase scaffold activity / 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 / type B pancreatic cell proliferation / labyrinthine layer development / MAP-kinase scaffold activity / cerebellar cortex formation / Signaling by MAP2K mutants / regulation of Golgi inheritance / 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 / protein kinase activator activity / ERBB2-ERBB3 signaling pathway / endodermal cell differentiation / face development / MAPK3 (ERK1) activation / Bergmann glial cell differentiation / MAP kinase kinase activity / thyroid gland development / Uptake and function of anthrax toxins / Schwann cell development / keratinocyte differentiation / ERK1 and ERK2 cascade / myelination / protein serine/threonine/tyrosine kinase activity / 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 / MAPK cascade / cellular senescence / Signaling by BRAF and RAF1 fusions / 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 phosphorylation / focal adhesion / protein serine kinase activity / 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 / Protein kinases ATP-binding region signature. ...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
Chem-3OR / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / TRIETHYLENE GLYCOL / Dual specificity mitogen-activated protein kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.8 Å
AuthorsLukacs, C.M. / Janson, C. / Schuck, V. / Belunis, C.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Design and synthesis of novel allosteric MEK inhibitor CH4987655 as an orally available anticancer agent.
Authors: Isshiki, Y. / Kohchi, Y. / Iikura, H. / Matsubara, Y. / Asoh, K. / Murata, T. / Kohchi, M. / Mizuguchi, E. / Tsujii, S. / Hattori, K. / Miura, T. / Yoshimura, Y. / Aida, S. / Miwa, M. / ...Authors: Isshiki, Y. / Kohchi, Y. / Iikura, H. / Matsubara, Y. / Asoh, K. / Murata, T. / Kohchi, M. / Mizuguchi, E. / Tsujii, S. / Hattori, K. / Miura, T. / Yoshimura, Y. / Aida, S. / Miwa, M. / Saitoh, R. / Murao, N. / Okabe, H. / Belunis, C. / Janson, C. / Lukacs, C. / Schuck, V. / Shimma, N.
History
DepositionSep 7, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 2, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Aug 23, 2017Group: Data collection / Refinement description / Source and taxonomy
Category: diffrn_detector / entity_src_gen / software / Item: _diffrn_detector.detector
Revision 1.3Feb 21, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / struct_conn / 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 / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _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)36,06211
Polymers34,2391
Non-polymers1,82210
Water70339
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
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)72,12422
Polymers68,4792
Non-polymers3,64520
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation5_555x-y,-y,-z+2/31
Buried area7400 Å2
ΔGint-190 kcal/mol
Surface area23470 Å2
MethodPISA
Unit cell
Length a, b, c (Å)136.670, 136.670, 60.906
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number152
Space group name H-MP3121

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 34239.438 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 62-270, 303-393
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

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Non-polymers , 6 types, 49 molecules

#2: Chemical ChemComp-ANP / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER


Mass: 506.196 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H17N6O12P3 / Comment: AMP-PNP, energy-carrying molecule analogue*YM
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-3OR / 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)-5-[(3-oxo-1,2-oxazinan-2-yl)methyl]benzamide


Mass: 565.282 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H19F3IN3O5
#5: Chemical ChemComp-PGE / TRIETHYLENE GLYCOL / Polyethylene glycol


Mass: 150.173 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14O4
#6: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 39 / 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: 4.8 Å3/Da / Density % sol: 74.35 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 2M Ammonium sulfate, 0.1M HEPES, pH 7.5, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.9793 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Aug 6, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 2.8→42.44 Å / Num. all: 16367 / Num. obs: 16356 / % possible obs: 99.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 11 % / Biso Wilson estimate: 81.1 Å2 / Rsym value: 0.168 / Net I/σ(I): 1.5
Reflection shellResolution: 2.8→2.95 Å / Redundancy: 11.2 % / Mean I/σ(I) obs: 1.5 / Num. unique all: 2367 / Rsym value: 0.447 / % possible all: 99.9

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Processing

Software
NameVersionClassification
CNX2005refinement
DENZOdata reduction
SCALAdata scaling
CNX2005phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.8→39.45 Å / Rfactor Rfree error: 0.01 / Data cutoff high absF: 919200.1 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.277 828 5.1 %RANDOM
Rwork0.234 ---
obs0.236 16352 99.7 %-
all-16352 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 48.1171 Å2 / ksol: 0.360087 e/Å3
Displacement parametersBiso mean: 53.7 Å2
Baniso -1Baniso -2Baniso -3
1--14.79 Å2-2.03 Å20 Å2
2---14.79 Å20 Å2
3---29.59 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.51 Å0.44 Å
Luzzati d res low-5 Å
Luzzati sigma a0.63 Å0.53 Å
Refinement stepCycle: LAST / Resolution: 2.8→39.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2188 0 104 39 2331
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.007
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg0.9
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d20.5
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.65
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.231.5
X-RAY DIFFRACTIONc_mcangle_it2.092
X-RAY DIFFRACTIONc_scbond_it2.112
X-RAY DIFFRACTIONc_scangle_it3.352.5
Refine LS restraints NCSNCS model details: NONE
LS refinement shellResolution: 2.8→2.92 Å / Rfactor Rfree error: 0.053 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.518 96 4.9 %
Rwork0.402 1852 -
obs--68.5 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paprotein.top
X-RAY DIFFRACTION2water_rep.parawater.top
X-RAY DIFFRACTION3ion.paramion.top
X-RAY DIFFRACTION4lig.parlig.top
X-RAY DIFFRACTION5anp2.paranp2.top

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