+Open data
-Basic information
Entry | Database: PDB / ID: 4u81 | ||||||
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Title | MEK1 Kinase bound to small molecule inhibitor G659 | ||||||
Components | Dual specificity mitogen-activated protein kinase kinase 1 | ||||||
Keywords | TRANSFERASE/TRANSFERASE Inhibitor / Kinase / Complex / Inhibitor / 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 / 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 / regulation of stress-activated MAPK cascade / positive regulation of axonogenesis / Frs2-mediated activation / ERBB2-ERBB3 signaling pathway / protein kinase activator activity / endodermal cell differentiation / MAPK3 (ERK1) activation / face development / MAP kinase kinase activity / Bergmann glial cell differentiation / thyroid gland development / Uptake and function of anthrax toxins / Schwann cell development / keratinocyte differentiation / Signal transduction by L1 / ERK1 and ERK2 cascade / protein serine/threonine/tyrosine kinase activity / myelination / protein serine/threonine kinase activator activity / MAP3K8 (TPL2)-dependent MAPK1/3 activation / insulin-like growth factor receptor signaling pathway / thymus development / cell motility / RAF activation / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / positive regulation of protein serine/threonine kinase activity / cellular senescence / 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 / Signaling by BRAF and RAF1 fusions / late endosome / heart development / protein tyrosine kinase activity / scaffold protein binding / 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: 2.701 Å | ||||||
Authors | Robarge, K.D. / Ultsch, M.H. / Weismann, C. | ||||||
Citation | Journal: Bioorg.Med.Chem.Lett. / Year: 2014 Title: Structure based design of novel 6,5 heterobicyclic mitogen-activated protein kinase kinase (MEK) inhibitors leading to the discovery of imidazo[1,5-a] pyrazine G-479. Authors: Robarge, K.D. / Lee, W. / Eigenbrot, C. / Ultsch, M. / Wiesmann, C. / Heald, R. / Price, S. / Hewitt, J. / Jackson, P. / Savy, P. / Burton, B. / Choo, E.F. / Pang, J. / Boggs, J. / Yang, A. ...Authors: Robarge, K.D. / Lee, W. / Eigenbrot, C. / Ultsch, M. / Wiesmann, C. / Heald, R. / Price, S. / Hewitt, J. / Jackson, P. / Savy, P. / Burton, B. / Choo, E.F. / Pang, J. / Boggs, J. / Yang, A. / Yang, X. / Baumgardner, M. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 4u81.cif.gz | 136.4 KB | Display | PDBx/mmCIF format |
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PDB format | pdb4u81.ent.gz | 103.7 KB | Display | PDB format |
PDBx/mmJSON format | 4u81.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 4u81_validation.pdf.gz | 1013.9 KB | Display | wwPDB validaton report |
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Full document | 4u81_full_validation.pdf.gz | 1018 KB | Display | |
Data in XML | 4u81_validation.xml.gz | 13.6 KB | Display | |
Data in CIF | 4u81_validation.cif.gz | 17.9 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/u8/4u81 ftp://data.pdbj.org/pub/pdb/validation_reports/u8/4u81 | HTTPS FTP |
-Related structure data
Related structure data | 4u7zC 4u80C 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 on special symmetry positions |
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-Components
#1: Protein | Mass: 37929.625 Da / Num. of mol.: 1 / Fragment: Kinase domain (UNP residues 62-393) Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Cell line: E. coli / Gene: MAP2K1, MEK1, PRKMK1 / Plasmid: pET24B / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta 2 pLysS References: UniProt: Q02750, mitogen-activated protein kinase kinase |
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#2: Chemical | ChemComp-MG / |
#3: Chemical | ChemComp-3EY / |
#4: Chemical | ChemComp-ANP / |
#5: Water | ChemComp-HOH / |
-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 3.32 Å3/Da / Density % sol: 62.95 % |
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Crystal grow | Temperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6.9 Details: The protein was concentrated to 15mg/ml and incubated with 10 fold molar excess inhibitor plus 1mM MgAMP-PNP before crystallization. MEK1 crystals grew from hanging drop vapor diffusion ...Details: The protein was concentrated to 15mg/ml and incubated with 10 fold molar excess inhibitor plus 1mM MgAMP-PNP before crystallization. MEK1 crystals grew from hanging drop vapor diffusion using 12% w/v PEG 8000, 0.4M NH4H2PO4 and 0.1M HEPES pH 6.9 at 18 degC. |
-Data collection
Diffraction | Mean temperature: 93 K |
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Diffraction source | Source: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.987 Å |
Detector | Type: ADSC QUANTUM 315r / Detector: CCD / Date: Dec 5, 2007 |
Radiation | Monochromator: Asymmetric curved crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.987 Å / Relative weight: 1 |
Reflection | Resolution: 2.7→20 Å / Num. all: 13584 / Num. obs: 13584 / % possible obs: 99.9 % / Observed criterion σ(I): 2 / Redundancy: 5.7 % / Biso Wilson estimate: 56.95 Å2 / Rsym value: 0.078 / Net I/av σ(I): 30.2 / Net I/σ(I): 36.2 |
Reflection shell | Resolution: 2.7→2.79 Å / Redundancy: 5.7 % / Rmerge(I) obs: 0.75 / Mean I/σ(I) obs: 2.7 / % possible all: 100 |
-Processing
Software | Name: PHENIX / Version: (phenix.refine: 1.8.2_1309) / Classification: refinement | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 1S9J Resolution: 2.701→19.716 Å / SU ML: 0.35 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 22.8 / Stereochemistry target values: ML
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Solvent computation | Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 2.701→19.716 Å
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Refine LS restraints |
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LS refinement shell |
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Refinement TLS params. | Method: refined / Refine-ID: X-RAY DIFFRACTION
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Refinement TLS group |
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