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Yorodumi- PDB-3ow3: Discovery of dihydrothieno- and dihydrofuropyrimidines as potent ... -
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-Basic information
Entry | Database: PDB / ID: 3ow3 | ||||||
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Title | Discovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors | ||||||
Components |
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Keywords | TRANSFERASE/TRANSFERASE inhibitor / cyclic-AMP dependent protein kinase / TRANSFERASE-TRANSFERASE inhibitor complex | ||||||
Function / homology | Function and homology information spontaneous exocytosis of neurotransmitter / PKA activation in glucagon signalling / CREB1 phosphorylation through the activation of Adenylate Cyclase / negative regulation of meiotic cell cycle / HDL assembly / DARPP-32 events / Rap1 signalling / PKA activation / Vasopressin regulates renal water homeostasis via Aquaporins / Regulation of insulin secretion ...spontaneous exocytosis of neurotransmitter / PKA activation in glucagon signalling / CREB1 phosphorylation through the activation of Adenylate Cyclase / negative regulation of meiotic cell cycle / HDL assembly / DARPP-32 events / Rap1 signalling / PKA activation / Vasopressin regulates renal water homeostasis via Aquaporins / Regulation of insulin secretion / GPER1 signaling / Hedgehog 'off' state / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Loss of Nlp from mitotic centrosomes / Recruitment of mitotic centrosome proteins and complexes / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / AURKA Activation by TPX2 / MAPK6/MAPK4 signaling / GLI3 is processed to GLI3R by the proteasome / Factors involved in megakaryocyte development and platelet production / Regulation of PLK1 Activity at G2/M Transition / Interleukin-3, Interleukin-5 and GM-CSF signaling / CD209 (DC-SIGN) signaling / Mitochondrial protein degradation / RET signaling / Ion homeostasis / VEGFA-VEGFR2 Pathway / regulation of cellular respiration / regulation of protein processing / protein localization to lipid droplet / regulation of bicellular tight junction assembly / cellular response to parathyroid hormone stimulus / cAMP-dependent protein kinase inhibitor activity / cAMP-dependent protein kinase / cellular response to cold / regulation of osteoblast differentiation / sperm capacitation / cAMP-dependent protein kinase activity / ciliary base / negative regulation of glycolytic process through fructose-6-phosphate / cAMP-dependent protein kinase complex / AMP-activated protein kinase activity / negative regulation of protein import into nucleus / postsynaptic modulation of chemical synaptic transmission / cellular response to glucagon stimulus / protein kinase A regulatory subunit binding / plasma membrane raft / protein kinase A catalytic subunit binding / axoneme / mesoderm formation / sperm flagellum / regulation of proteasomal protein catabolic process / negative regulation of smoothened signaling pathway / positive regulation of gluconeogenesis / sperm midpiece / negative regulation of TORC1 signaling / regulation of synaptic transmission, glutamatergic / regulation of G2/M transition of mitotic cell cycle / protein kinase A signaling / protein serine/threonine/tyrosine kinase activity / protein export from nucleus / acrosomal vesicle / positive regulation of protein export from nucleus / neural tube closure / cellular response to glucose stimulus / modulation of chemical synaptic transmission / neuromuscular junction / positive regulation of insulin secretion / adenylate cyclase-activating G protein-coupled receptor signaling pathway / small GTPase binding / mRNA processing / presynapse / manganese ion binding / cellular response to heat / peptidyl-serine phosphorylation / postsynapse / dendritic spine / regulation of cell cycle / protein kinase activity / nuclear speck / protein domain specific binding / protein serine kinase activity / protein serine/threonine kinase activity / centrosome / glutamatergic synapse / ubiquitin protein ligase binding / positive regulation of cell population proliferation / protein-containing complex binding / protein kinase binding / perinuclear region of cytoplasm / negative regulation of transcription by RNA polymerase II / magnesium ion binding / protein-containing complex / mitochondrion / nucleoplasm / ATP binding / nucleus / plasma membrane Similarity search - Function | ||||||
Biological species | Mus musculus (house mouse) | ||||||
Method | X-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.9 Å | ||||||
Authors | Dizon, F. / Wu, W. / Vigers, G.P.A. / Brandhuber, B.J. | ||||||
Citation | Journal: Bioorg.Med.Chem.Lett. / Year: 2010 Title: Discovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors. Authors: Bencsik, J.R. / Xiao, D. / Blake, J.F. / Kallan, N.C. / Mitchell, I.S. / Spencer, K.L. / Xu, R. / Gloor, S.L. / Martinson, M. / Risom, T. / Woessner, R.D. / Dizon, F. / Wu, W.I. / Vigers, G. ...Authors: Bencsik, J.R. / Xiao, D. / Blake, J.F. / Kallan, N.C. / Mitchell, I.S. / Spencer, K.L. / Xu, R. / Gloor, S.L. / Martinson, M. / Risom, T. / Woessner, R.D. / Dizon, F. / Wu, W.I. / Vigers, G.P. / Brandhuber, B.J. / Skelton, N.J. / Prior, W.W. / Murray, L.J. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 3ow3.cif.gz | 97.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb3ow3.ent.gz | 72.5 KB | Display | PDB format |
PDBx/mmJSON format | 3ow3.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/ow/3ow3 ftp://data.pdbj.org/pub/pdb/validation_reports/ow/3ow3 | HTTPS FTP |
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-Related structure data
Related structure data | 3ow4C 1atpS 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: 40657.316 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Mus musculus (house mouse) / Gene: Prkaca, Pkaca / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P05132, cAMP-dependent protein kinase |
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#2: Protein/peptide | Mass: 2226.411 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Mus musculus (house mouse) / References: UniProt: P63248 |
#3: Chemical | ChemComp-SMY / ( |
#4: 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: 2.65 Å3/Da / Density % sol: 53.54 % |
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Crystal grow | Temperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8 Details: 6.6mg/ml PKA with 0.25mM PKI, 50mM bicine, 150mM ammonium acetate, 2mM DTT, 8% PEG400, 11% methanol, pH 8.0, VAPOR DIFFUSION, HANGING DROP, temperature 277K |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT |
Detector | Type: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Jun 15, 2005 |
Radiation | Monochromator: Confocal mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Relative weight: 1 |
Reflection | Resolution: 1.9→30 Å / Num. all: 36407 / Num. obs: 32859 / % possible obs: 90 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 6.6 % / Rmerge(I) obs: 0.067 / Rsym value: 0.061 / Net I/σ(I): 13.9 |
Reflection shell | Resolution: 1.9→2 Å / Redundancy: 3.9 % / Rmerge(I) obs: 0.151 / Mean I/σ(I) obs: 5.4 / Num. unique all: 5183 / Rsym value: 0.133 / % possible all: 56.1 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: PDB entry 1ATP Resolution: 1.9→23.49 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.93 / SU B: 2.572 / SU ML: 0.078 / Cross valid method: THROUGHOUT / ESU R Free: 0.133 / Stereochemistry target values: MAXIMUM LIKELIHOOD
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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: BABINET MODEL WITH MASK | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 29.113 Å2
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Refinement step | Cycle: LAST / Resolution: 1.9→23.49 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 1.9→1.949 Å / Total num. of bins used: 20
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