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- PDB-3ow3: Discovery of dihydrothieno- and dihydrofuropyrimidines as potent ... -

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Basic information

Entry
Database: PDB / ID: 3ow3
TitleDiscovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors
Components
  • cAMP-dependent protein kinase catalytic subunit alphaCAMP-dependent pathway
  • cAMP-dependent protein kinase inhibitor alphaCAMP-dependent pathway
KeywordsTRANSFERASE/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 / MAPK6/MAPK4 signaling / GLI3 is processed to GLI3R by the proteasome / AURKA Activation by TPX2 / 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 / RET signaling / Ion homeostasis / VEGFA-VEGFR2 Pathway / nucleotide-activated protein kinase complex / 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 / sperm capacitation / regulation of osteoblast differentiation / cAMP-dependent protein kinase activity / ciliary base / cAMP-dependent protein kinase complex / negative regulation of glycolytic process through fructose-6-phosphate / 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 / axoneme / protein kinase A catalytic subunit binding / plasma membrane raft / mesoderm formation / sperm flagellum / negative regulation of smoothened signaling pathway / regulation of proteasomal protein catabolic process / protein kinase A signaling / positive regulation of gluconeogenesis / regulation of synaptic transmission, glutamatergic / negative regulation of TORC1 signaling / sperm midpiece / regulation of G2/M transition of mitotic cell cycle / protein export from nucleus / protein serine/threonine/tyrosine kinase activity / acrosomal vesicle / positive regulation of protein export from nucleus / neural tube closure / cellular response to glucose stimulus / modulation of chemical synaptic transmission / neuromuscular junction / adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of insulin secretion / mRNA processing / small GTPase binding / presynapse / cellular response to heat / manganese ion binding / postsynapse / peptidyl-serine phosphorylation / 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 / magnesium ion binding / negative regulation of transcription by RNA polymerase II / protein-containing complex / mitochondrion / nucleoplasm / ATP binding / nucleus / plasma membrane
Similarity search - Function
cAMP-dependent protein kinase inhibitor / cAMP-dependent protein kinase inhibitor / cAMP-dependent protein kinase catalytic subunit / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 ...cAMP-dependent protein kinase inhibitor / cAMP-dependent protein kinase inhibitor / cAMP-dependent protein kinase catalytic subunit / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / 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 / cAMP-dependent protein kinase catalytic subunit alpha / cAMP-dependent protein kinase inhibitor alpha
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.9 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
Revision 1.2Dec 12, 2012Group: Other
Revision 1.3Mar 13, 2013Group: Other
Revision 1.4Sep 6, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: cAMP-dependent protein kinase catalytic subunit alpha
B: cAMP-dependent protein kinase inhibitor alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,3063
Polymers42,8842
Non-polymers4231
Water7,260403
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1920 Å2
ΔGint-4 kcal/mol
Surface area16230 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.249, 79.463, 98.118
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein cAMP-dependent protein kinase catalytic subunit alpha / CAMP-dependent pathway / PKA C-alpha


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
#2: Protein/peptide cAMP-dependent protein kinase inhibitor alpha / CAMP-dependent pathway / PKI-alpha / cAMP-dependent protein kinase inhibitor / muscle/brain isoform


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 / (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.: 1 / Source method: obtained synthetically / Formula: C22H26N6OS
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 403 / Source method: isolated from a natural source / Formula: H2O

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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: 2.65 Å3/Da / Density % sol: 53.54 %
Crystal growTemperature: 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

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Jun 15, 2005
RadiationMonochromator: Confocal mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 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 shellResolution: 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

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Processing

Software
NameVersionClassification
CrystalCleardata collection
MOLREPphasing
REFMAC5.5.0109refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1ATP

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
RfactorNum. reflection% reflectionSelection details
Rfree0.20981 1631 5 %RANDOM
Rwork0.16403 ---
obs0.16626 32818 89.6 %-
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: 29.113 Å2
Baniso -1Baniso -2Baniso -3
1-0.66 Å20 Å20 Å2
2---0.15 Å20 Å2
3----0.51 Å2
Refinement stepCycle: LAST / Resolution: 1.9→23.49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2925 0 30 403 3358
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0280.0223032
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg2.0981.9664094
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.955353
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.24223.826149
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.01315.028538
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.851518
X-RAY DIFFRACTIONr_chiral_restr0.1790.2426
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.0212311
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_it1.3621.51765
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.31922848
X-RAY DIFFRACTIONr_scbond_it3.62231267
X-RAY DIFFRACTIONr_scangle_it5.4314.51246
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.9→1.949 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.264 71 -
Rwork0.164 1259 -
obs--100 %

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