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- PDB-3v01: Discovery of Novel Allosteric MEK Inhibitors Possessing Classical... -

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Basic information

Entry
Database: PDB / ID: 3v01
TitleDiscovery of Novel Allosteric MEK Inhibitors Possessing Classical and Non-classical Bidentate Ser212 Interactions.
ComponentsDual specificity mitogen-activated protein kinase kinase 1
KeywordsTransferase/Inhibitor / Kinase / 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 / labyrinthine layer development / type B pancreatic cell proliferation / 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 / labyrinthine layer development / type B pancreatic cell proliferation / 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 / ERBB2-ERBB3 signaling pathway / protein kinase activator activity / 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 / neuron differentiation / positive regulation of protein serine/threonine kinase activity / 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 / early endosome / positive regulation of ERK1 and ERK2 cascade / protein kinase activity / negative regulation of cell population proliferation / protein phosphorylation / 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 / 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-3V0 / ADENOSINE-5'-TRIPHOSPHATE / Dual specificity mitogen-activated protein kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.705 Å
AuthorsHeald, R. / Jackson, P. / Savy, P. / Jones, M. / Gancia, E. / Burton, B. / Newman, R. / Boggs, J. / Chan, E. / Chan, J. ...Heald, R. / Jackson, P. / Savy, P. / Jones, M. / Gancia, E. / Burton, B. / Newman, R. / Boggs, J. / Chan, E. / Chan, J. / Choo, E. / Merchant, M. / Ultsch, M. / Wiesmann, C. / Belvin, M. / Price, S.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Discovery of Novel Allosteric Mitogen-Activated Protein Kinase Kinase (MEK) 1,2 Inhibitors Possessing Bidentate Ser212 Interactions.
Authors: Heald, R.A. / Jackson, P. / Savy, P. / Jones, M. / Gancia, E. / Burton, B. / Newman, R. / Boggs, J. / Chan, E. / Chan, J. / Choo, E. / Merchant, M. / Rudewicz, P. / Ultsch, M. / Wiesmann, C. ...Authors: Heald, R.A. / Jackson, P. / Savy, P. / Jones, M. / Gancia, E. / Burton, B. / Newman, R. / Boggs, J. / Chan, E. / Chan, J. / Choo, E. / Merchant, M. / Rudewicz, P. / Ultsch, M. / Wiesmann, C. / Yue, Q. / Belvin, M. / Price, S.
History
DepositionDec 7, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 9, 2012Provider: repository / Type: Initial release
Revision 1.1Jul 18, 2012Group: Database references
Revision 1.2Sep 13, 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 / 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_asym_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_asym_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_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)38,9494
Polymers37,9311
Non-polymers1,0193
Water0
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)81.619, 81.619, 129.521
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 / MKK1 / ERK activator kinase 1 / MAPK/ERK kinase 1 / MEK 1


Mass: 37930.609 Da / Num. of mol.: 1 / Fragment: UNP residues 62-393
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAP2K1, MEK1, PRKMK1 / Plasmid: pET24b / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta 2
References: UniProt: Q02750, mitogen-activated protein kinase kinase
#2: Chemical ChemComp-3V0 / N-{[(2R)-2,3-dihydroxypropyl]oxy}-3-[(2-fluoro-4-iodophenyl)amino]furo[3,2-c]pyridine-2-carboxamide


Mass: 487.221 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H15FIN3O5
#3: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE / Adenosine triphosphate


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


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg

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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: 3.28 Å3/Da / Density % sol: 62.54 %
Crystal growTemperature: 286 K / Method: vapor diffusion, hanging drop / pH: 7.2
Details: 16-20% w/v PEG8K, 0.1M HEPES, 250mM NH4H2PO4, 1mM TCEP, pH 7.2, VAPOR DIFFUSION, HANGING DROP, temperature 286K

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Data collection

DiffractionMean temperature: 200 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jun 9, 2006
RadiationMonochromator: Si 111 CHANNEL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.7→50 Å / Num. all: 13370 / Num. obs: 13330 / % possible obs: 99.7 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 3 / Redundancy: 4.8 % / Biso Wilson estimate: 71.66 Å2 / Rsym value: 0.057 / Net I/σ(I): 24.23

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
AMoREphasing
REFMAC5.2.0005refinement
HKL-2000data reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1S9J

1s9j


Resolution: 2.705→20 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.92 / SU B: 23.079 / SU ML: 0.213 / Cross valid method: THROUGHOUT / σ(F): 2 / ESU R: 0.425 / ESU R Free: 0.282 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23977 640 4.8 %RANDOM
Rwork0.187 ---
obs0.18942 12675 99.74 %-
all-13370 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 85.632 Å2
Baniso -1Baniso -2Baniso -3
1-2.3 Å21.15 Å20 Å2
2--2.3 Å20 Å2
3----3.45 Å2
Refinement stepCycle: LAST / Resolution: 2.705→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2261 0 59 0 2320
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0222369
X-RAY DIFFRACTIONr_bond_other_d0.0020.022174
X-RAY DIFFRACTIONr_angle_refined_deg1.6282.0123200
X-RAY DIFFRACTIONr_angle_other_deg0.79435083
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7465286
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.97624.43397
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.00815425
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.3461512
X-RAY DIFFRACTIONr_chiral_restr0.0790.2349
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.022553
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02448
X-RAY DIFFRACTIONr_nbd_refined0.2160.2500
X-RAY DIFFRACTIONr_nbd_other0.1720.22119
X-RAY DIFFRACTIONr_nbtor_refined0.1850.21148
X-RAY DIFFRACTIONr_nbtor_other0.0860.21404
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1480.245
X-RAY DIFFRACTIONr_metal_ion_refined0.0540.22
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1030.27
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1550.230
X-RAY DIFFRACTIONr_mcbond_it3.5592.51450
X-RAY DIFFRACTIONr_mcbond_other0.6952.5586
X-RAY DIFFRACTIONr_mcangle_it5.41452318
X-RAY DIFFRACTIONr_scbond_it3.5482.51024
X-RAY DIFFRACTIONr_scangle_it5.6385882
LS refinement shellResolution: 2.705→2.76 Å / Total num. of bins used: 25
RfactorNum. reflection% reflection
Rfree0.292 27 -
Rwork0.285 705 -
obs--98.26 %
Refinement TLS params.Method: refined / Origin x: 30.1506 Å / Origin y: 21.2187 Å / Origin z: -9.1333 Å
111213212223313233
T0.0051 Å20.144 Å2-0.0016 Å2--0.224 Å2-0.009 Å2--0.0058 Å2
L1.525 °20.2058 °2-0.8587 °2-1.1634 °20.5917 °2--5.5379 °2
S-0.2105 Å °0.2005 Å °-0.4247 Å °-0.1336 Å °0.0549 Å °0.2577 Å °-0.2677 Å °-0.2238 Å °0.1555 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A501 - 503
2X-RAY DIFFRACTION1A61 - 382

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