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Yorodumi- PDB-3v01: Discovery of Novel Allosteric MEK Inhibitors Possessing Classical... -
+Open data
-Basic information
Entry | Database: PDB / ID: 3v01 | ||||||
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Title | Discovery of Novel Allosteric MEK Inhibitors Possessing Classical and Non-classical Bidentate Ser212 Interactions. | ||||||
Components | Dual specificity mitogen-activated protein kinase kinase 1 | ||||||
Keywords | Transferase/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 / 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 / protein kinase activator activity / ERBB2-ERBB3 signaling pathway / 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 / Signaling by BRAF and RAF1 fusions / cellular senescence / 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 / signal transduction / endoplasmic reticulum / mitochondrion / ATP binding / nucleus / plasma membrane / cytosol Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.705 Å | ||||||
Authors | Heald, 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. | ||||||
Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 3v01.cif.gz | 135.7 KB | Display | PDBx/mmCIF format |
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PDB format | pdb3v01.ent.gz | 104.5 KB | Display | PDB format |
PDBx/mmJSON format | 3v01.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 3v01_validation.pdf.gz | 1 MB | Display | wwPDB validaton report |
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Full document | 3v01_full_validation.pdf.gz | 1 MB | Display | |
Data in XML | 3v01_validation.xml.gz | 12.9 KB | Display | |
Data in CIF | 3v01_validation.cif.gz | 16.7 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/v0/3v01 ftp://data.pdbj.org/pub/pdb/validation_reports/v0/3v01 | HTTPS FTP |
-Related structure data
Related structure data | 3v04C 1s9jS C: citing same article (ref.) S: Starting model for refinement |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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Unit cell |
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-Components
#1: Protein | 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 |
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#2: Chemical | ChemComp-3V0 / |
#3: Chemical | ChemComp-ATP / |
#4: Chemical | ChemComp-MG / |
-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 3.28 Å3/Da / Density % sol: 62.54 % |
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Crystal grow | Temperature: 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 |
-Data collection
Diffraction | Mean temperature: 200 K |
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Diffraction source | Source: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å |
Detector | Type: ADSC QUANTUM 315 / Detector: CCD / Date: Jun 9, 2006 |
Radiation | Monochromator: Si 111 CHANNEL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1 Å / Relative weight: 1 |
Reflection | Resolution: 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 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: PDB ENTRY 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
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Solvent computation | Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 85.632 Å2
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Refinement step | Cycle: LAST / Resolution: 2.705→20 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 2.705→2.76 Å / Total num. of bins used: 25
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Refinement TLS params. | Method: refined / Origin x: 30.1506 Å / Origin y: 21.2187 Å / Origin z: -9.1333 Å
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Refinement TLS group |
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