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Yorodumi- PDB-4an2: Crystal structures of human MEK1 with carboxamide-based allosteri... -
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-Basic information
Entry | Database: PDB / ID: 4an2 | ||||||
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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 / 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 / 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 / myelination / protein serine/threonine/tyrosine kinase activity / 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 / cellular senescence / MAPK cascade / 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 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: 2.5 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 | 4an2.cif.gz | 73.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb4an2.ent.gz | 53.5 KB | Display | PDB format |
PDBx/mmJSON format | 4an2.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 4an2_validation.pdf.gz | 1002 KB | Display | wwPDB validaton report |
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Full document | 4an2_full_validation.pdf.gz | 1009.8 KB | Display | |
Data in XML | 4an2_validation.xml.gz | 14.2 KB | Display | |
Data in CIF | 4an2_validation.cif.gz | 18.6 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/an/4an2 ftp://data.pdbj.org/pub/pdb/validation_reports/an/4an2 | 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 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-EUI / [ |
#3: Chemical | ChemComp-ACP / |
#4: Chemical | ChemComp-MG / |
#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 % |
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Crystal grow | pH: 8.9 Details: MEK1 (8 MG/ML) WAS INCUBATED WITH INHIBITOR (300 MICROMOLAR FINAL CONCENTRATION) AND AMPPCP (2.8 MM FINAL CONCENTRATION) FOR TWO HOURS ON ICE, FOLLOWED BY CRYSTALLIZION VS. 26.5% PEG-2000 ...Details: MEK1 (8 MG/ML) WAS INCUBATED WITH INHIBITOR (300 MICROMOLAR FINAL CONCENTRATION) AND AMPPCP (2.8 MM FINAL CONCENTRATION) FOR TWO HOURS ON ICE, FOLLOWED BY CRYSTALLIZION VS. 26.5% PEG-2000 MME, 0.1 M TRIMETHYLAMINE N- OXIDE AND 0.1 M TRIS (PH 8.9) |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: SYNCHROTRON / Site: ALS / Beamline: 8.2.1 / Wavelength: 1 |
Detector | Type: ADSC QUANTUM 315r / Detector: CCD / Date: Nov 15, 2005 |
Radiation | Monochromator: DOUBLE CRYSTAL, SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1 Å / Relative weight: 1 |
Reflection | Resolution: 2.5→54.39 Å / Num. obs: 12819 / % possible obs: 99.8 % / Observed criterion σ(I): 2 / Redundancy: 4.4 % / Rmerge(I) obs: 0.07 / Net I/σ(I): 15.2 |
Reflection shell | Resolution: 2.5→2.68 Å / Redundancy: 4.2 % / Rmerge(I) obs: 0.56 / Mean I/σ(I) obs: 2.3 / % possible all: 99.9 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: IN HOUSE MEK1-AMPPCP STRUCTURE Resolution: 2.5→94.07 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.888 / SU B: 13.071 / SU ML: 0.286 / Cross valid method: THROUGHOUT / ESU R: 0.66 / ESU R Free: 0.352 / 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: 53.06 Å2
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Refinement step | Cycle: LAST / Resolution: 2.5→94.07 Å
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