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- PDB-3ow4: Discovery of dihydrothieno- and dihydrofuropyrimidines as potent ... -

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Basic information

Entry
Database: PDB / ID: 3ow4
TitleDiscovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors
Components
  • GSK 3 beta peptide
  • RAC-alpha serine/threonine-protein kinase
KeywordsTRANSFERASE/TRANSFERASE inhibitor / SERINE-THREONINE KINASE / TRANSFERASE / TRANSFERASE-TRANSFERASE inhibitor complex
Function / homology
Function and homology information


glycogen cell differentiation involved in embryonic placenta development / regulation of tRNA methylation / response to insulin-like growth factor stimulus / potassium channel activator activity / negative regulation of protein localization to lysosome / positive regulation of protein localization to endoplasmic reticulum / maintenance of protein location in mitochondrion / negative regulation of lymphocyte migration / cellular response to decreased oxygen levels / regulation of type B pancreatic cell development ...glycogen cell differentiation involved in embryonic placenta development / regulation of tRNA methylation / response to insulin-like growth factor stimulus / potassium channel activator activity / negative regulation of protein localization to lysosome / positive regulation of protein localization to endoplasmic reticulum / maintenance of protein location in mitochondrion / negative regulation of lymphocyte migration / cellular response to decreased oxygen levels / regulation of type B pancreatic cell development / AKT-mediated inactivation of FOXO1A / maternal placenta development / Negative regulation of the PI3K/AKT network / negative regulation of long-chain fatty acid import across plasma membrane / establishment of protein localization to mitochondrion / negative regulation of fatty acid beta-oxidation / AKT phosphorylates targets in the nucleus / regulation of glycogen biosynthetic process / cellular response to oxidised low-density lipoprotein particle stimulus / regulation of microtubule anchoring at centrosome / negative regulation of glycogen (starch) synthase activity / neuron projection organization / negative regulation of mesenchymal stem cell differentiation / beta-catenin destruction complex disassembly / negative regulation of type B pancreatic cell development / negative regulation of cilium assembly / positive regulation of I-kappaB phosphorylation / superior temporal gyrus development / Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA / positive regulation of protein localization to cilium / negative regulation of glycogen biosynthetic process / response to fluid shear stress / RUNX2 regulates genes involved in cell migration / negative regulation of dopaminergic neuron differentiation / positive regulation of organ growth / maintenance of cell polarity / positive regulation of protein localization to centrosome / : / positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / MTOR signalling / fibroblast migration / interleukin-18-mediated signaling pathway / positive regulation of sodium ion transport / positive regulation of cilium assembly / mammary gland epithelial cell differentiation / negative regulation of endopeptidase activity / negative regulation of protein acetylation / negative regulation of protein serine/threonine kinase activity / APC truncation mutants have impaired AXIN binding / AXIN missense mutants destabilize the destruction complex / Truncations of AMER1 destabilize the destruction complex / beta-catenin destruction complex / RAB GEFs exchange GTP for GDP on RABs / positive regulation of glucose metabolic process / tau-protein kinase / CRMPs in Sema3A signaling / heart valve development / positive regulation of endodeoxyribonuclease activity / regulation of microtubule-based process / response to growth factor / cellular response to granulocyte macrophage colony-stimulating factor stimulus / positive regulation of protein localization to cell surface / regulation of protein export from nucleus / protein serine/threonine kinase inhibitor activity / negative regulation of leukocyte cell-cell adhesion / phosphatidylinositol-3,4-bisphosphate binding / Beta-catenin phosphorylation cascade / Signaling by GSK3beta mutants / CTNNB1 S33 mutants aren't phosphorylated / CTNNB1 S37 mutants aren't phosphorylated / CTNNB1 S45 mutants aren't phosphorylated / CTNNB1 T41 mutants aren't phosphorylated / peripheral nervous system myelin maintenance / Maturation of nucleoprotein / sphingosine-1-phosphate receptor signaling pathway / cellular response to interleukin-3 / positive regulation of fibroblast migration / cell migration involved in sprouting angiogenesis / response to growth hormone / Wnt signalosome / negative regulation of protein localization to nucleus / anoikis / glycogen biosynthetic process / negative regulation of TOR signaling / regulation of long-term synaptic potentiation / Disassembly of the destruction complex and recruitment of AXIN to the membrane / Maturation of nucleoprotein / AKT phosphorylates targets in the cytosol / labyrinthine layer blood vessel development / execution phase of apoptosis / response to food / negative regulation of calcineurin-NFAT signaling cascade / positive regulation of cell-matrix adhesion / response to UV-A / regulation of myelination / regulation of postsynapse organization / regulation of axon extension / regulation of neuron projection development / G protein-coupled dopamine receptor signaling pathway / KSRP (KHSRP) binds and destabilizes mRNA
Similarity search - Function
Protein kinase B alpha, catalytic domain / Protein Kinase B, pleckstrin homology domain / Glycogen synthase kinase 3, catalytic domain / Protein kinase, C-terminal / Protein kinase C terminal domain / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / PH domain / PH domain profile. ...Protein kinase B alpha, catalytic domain / Protein Kinase B, pleckstrin homology domain / Glycogen synthase kinase 3, catalytic domain / Protein kinase, C-terminal / Protein kinase C terminal domain / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / PH domain / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / PH-like domain superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-SMY / RAC-alpha serine/threonine-protein kinase / Glycogen synthase kinase-3 beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsDizon, F. / Wu, W. / Vigers, G.P.A. / Brandhuber, B.J.
CitationJournal: 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
DepositionSep 17, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 10, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: RAC-alpha serine/threonine-protein kinase
B: RAC-alpha serine/threonine-protein kinase
C: GSK 3 beta peptide
D: GSK 3 beta peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)82,0256
Polymers81,1804
Non-polymers8452
Water3,081171
1
A: RAC-alpha serine/threonine-protein kinase
C: GSK 3 beta peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,0133
Polymers40,5902
Non-polymers4231
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1300 Å2
ΔGint-2 kcal/mol
Surface area15220 Å2
MethodPISA
2
B: RAC-alpha serine/threonine-protein kinase
D: GSK 3 beta peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,0133
Polymers40,5902
Non-polymers4231
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1280 Å2
ΔGint-0 kcal/mol
Surface area15500 Å2
MethodPISA
Unit cell
Length a, b, c (Å)86.427, 55.823, 91.354
Angle α, β, γ (deg.)90.00, 103.93, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein RAC-alpha serine/threonine-protein kinase / RAC-PK-alpha / Protein kinase B / PKB / Proto-oncogene c-Akt


Mass: 39466.969 Da / Num. of mol.: 2 / Mutation: S473D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AKT1, PKB, RAC / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P31749, non-specific serine/threonine protein kinase
#2: Protein/peptide GSK 3 beta peptide


Mass: 1123.220 Da / Num. of mol.: 2 / Source method: obtained synthetically / References: UniProt: P49841*PLUS
#3: Chemical ChemComp-SMY / (2R)-3-(1H-indol-3-yl)-1-{4-[(5S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]piperazin-1-yl}-1-oxopropan-2-amine


Mass: 422.546 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H26N6OS
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 171 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsTHERE IS A GLY -> SER SEQUENCE CONFLICT AT RESIDUE 478 IN UNIPROT SEQUENCE DATABASE.

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.63 Å3/Da / Density % sol: 53.32 %
Crystal growTemperature: 293 K / Method: under oil / pH: 7.5
Details: 8.3 mg/ml AKT1 protein, preincubated with 0.6 mM GSK3B peptide, 5 mM Mn-AMP-PNP. The precipitant was 20% PEG 4K, 15% isopropanol, 100 mM Hepes, pH 7.5, Under oil, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: May 11, 2005 / Details: Osmic confocal
RadiationMonochromator: Confocal mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.6→30 Å / Num. all: 26161 / Num. obs: 22796 / % possible obs: 86.7 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.5 % / Rmerge(I) obs: 0.051 / Rsym value: 0.043 / Net I/σ(I): 16.9
Reflection shellResolution: 2.6→2.74 Å / Redundancy: 2.7 % / Rmerge(I) obs: 0.107 / Mean I/σ(I) obs: 8.6 / Num. unique all: 3727 / Rsym value: 0.084 / % possible all: 50.3

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Processing

Software
NameVersionClassification
CrystalCleardata collection
MOLREPphasing
REFMAC5.5.0109refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.6→27.47 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.867 / SU B: 10.297 / SU ML: 0.23 / Cross valid method: THROUGHOUT / ESU R Free: 0.36 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.26756 1110 4.9 %RANDOM
Rwork0.19329 ---
obs0.19689 22769 86.3 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 47.824 Å2
Baniso -1Baniso -2Baniso -3
1-0.81 Å20 Å21.11 Å2
2--0.06 Å20 Å2
3----0.33 Å2
Refinement stepCycle: LAST / Resolution: 2.6→27.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5366 0 60 171 5597
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0225562
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.6651.9827492
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7195650
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.40323.333270
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.50115994
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.6251540
X-RAY DIFFRACTIONr_chiral_restr0.1060.2776
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0214238
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.7061.53258
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.37625242
X-RAY DIFFRACTIONr_scbond_it1.99132304
X-RAY DIFFRACTIONr_scangle_it3.3384.52250
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.6→2.667 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.309 46 -
Rwork0.199 832 -
obs--100 %

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