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Yorodumi- PDB-4an9: Crystal structures of human MEK1 with carboxamide-based allosteri... -
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-Basic information
Entry | Database: PDB / ID: 4an9 | ||||||
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Title | Crystal structures of human MEK1 with carboxamide-based allosteric inhibitor XL518 (GDC-0973), or related analogs. | ||||||
Components | DUAL SPECIFICITY MITOGEN-ACTIVATED PROTEIN KINASE KINASE 1 | ||||||
Keywords | TRANSFERASE / MAP2K1 / ATP-BINDING / ALLOSTERIC INHIBITION | ||||||
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 / 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 / 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 / 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 / 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 | ||||||
Biological species | HOMO SAPIENS (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å | ||||||
Authors | Rice, K.D. / Aay, N. / Anand, N.K. / Blazey, C.M. / Bowles, O.J. / Bussenius, J. / Costanzo, S. / Curtis, J.K. / Defina, S.C. / Dubenko, L. ...Rice, K.D. / Aay, N. / Anand, N.K. / Blazey, C.M. / Bowles, O.J. / Bussenius, J. / Costanzo, S. / Curtis, J.K. / Defina, S.C. / Dubenko, L. / Engst, S. / Joshi, A.A. / Kennedy, A.R. / Kim, A.I. / Koltun, E.S. / Lougheed, J.C. / Manalo, J.C.L. / Martini, J.F. / Nuss, J.M. / Peto, C.J. / Tsang, T.H. / Yu, P. / Johnston, S. | ||||||
Citation | Journal: Acs Med.Chem.Lett. / Year: 2012 Title: Novel Carboxamide-Based Allosteric Mek Inhibitors: Discovery and Optimization Efforts Toward Xl518 (Gdc-0973) Authors: Rice, K.D. / Aay, N. / Anand, N.K. / Blazey, C.M. / Bowles, O.J. / Bussenius, J. / Costanzo, S. / Curtis, J.K. / Defina, S.C. / Dubenko, L. / Engst, S. / Joshi, A.A. / Kennedy, A.R. / Kim, A. ...Authors: Rice, K.D. / Aay, N. / Anand, N.K. / Blazey, C.M. / Bowles, O.J. / Bussenius, J. / Costanzo, S. / Curtis, J.K. / Defina, S.C. / Dubenko, L. / Engst, S. / Joshi, A.A. / Kennedy, A.R. / Kim, A.I. / Koltun, E.S. / Lougheed, J.C. / Manalo, J.C.L. / Martini, J.F. / Nuss, J.M. / Peto, C.J. / Tsang, T.H. / Yu, P. / Johnston, S. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 4an9.cif.gz | 71.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb4an9.ent.gz | 52.2 KB | Display | PDB format |
PDBx/mmJSON format | 4an9.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 4an9_validation.pdf.gz | 1006.1 KB | Display | wwPDB validaton report |
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Full document | 4an9_full_validation.pdf.gz | 1015.7 KB | Display | |
Data in XML | 4an9_validation.xml.gz | 13.9 KB | Display | |
Data in CIF | 4an9_validation.cif.gz | 18.1 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/an/4an9 ftp://data.pdbj.org/pub/pdb/validation_reports/an/4an9 | HTTPS FTP |
-Related 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: 33614.730 Da / Num. of mol.: 1 / Fragment: PROTEIN KINASE DOMAIN, RESIDUES 61-262,305-392 / Mutation: YES Source method: isolated from a genetically manipulated source Details: DELETION OF AMINO ACID RESIDUES 263-304 / Source: (gene. exp.) HOMO SAPIENS (human) / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / Strain (production host): SF9 References: UniProt: Q02750, mitogen-activated protein kinase kinase |
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#2: Chemical | ChemComp-ACP / |
#3: Chemical | ChemComp-MG / |
#4: Chemical | ChemComp-2P7 / [ |
#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: 2.32 Å3/Da / Density % sol: 47 % / Description: NONE |
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Crystal grow | Method: vapor diffusion, sitting drop / pH: 8.9 Details: SITTING DROP VAPOR-DIFFUSION VS. 26.5 % PEG-2000 MME, 0.1 M TRIMETHYLAMINE N-OXIDE, 0.1 M TRIS (PH 8.9) |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: SYNCHROTRON / Site: SSRL / Beamline: BL9-1 / Wavelength: 0.97946 |
Detector | Type: ADSC QUANTUM 315r / Detector: CCD / Date: May 10, 2005 / Details: FLAT MIRROR, RH COATED |
Radiation | Monochromator: SI(311) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.97946 Å / Relative weight: 1 |
Reflection | Resolution: 2.8→49.39 Å / Num. obs: 8366 / % possible obs: 99.8 % / Observed criterion σ(I): 2 / Redundancy: 5.4 % / Rmerge(I) obs: 0.12 / Net I/σ(I): 11.3 |
Reflection shell | Resolution: 2.8→2.95 Å / Redundancy: 5.5 % / Rmerge(I) obs: 0.82 / Mean I/σ(I) obs: 2.3 / % possible all: 100 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: UNPUBLISHED MEK1-ATP COMPLEX Resolution: 2.8→49.4 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.85 / SU B: 17.67 / SU ML: 0.353 / Cross valid method: THROUGHOUT / ESU R Free: 0.476 / 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: 1.2 Å / Solvent model: MASK | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 50.373 Å2
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Refinement step | Cycle: LAST / Resolution: 2.8→49.4 Å
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Refine LS restraints |
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