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- PDB-3qkl: Spirochromane Akt Inhibitors -

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Basic information

Entry
Database: PDB / ID: 3qkl
TitleSpirochromane Akt Inhibitors
Components
  • Glycogen synthase kinase-3 beta
  • RAC-alpha serine/threonine-protein kinase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase Domain / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


regulation of tRNA methylation / negative regulation of protein maturation / response to insulin-like growth factor stimulus / mammalian oogenesis stage / regulation of glycogen biosynthetic process / positive regulation of protein localization to endoplasmic reticulum / negative regulation of lymphocyte migration / negative regulation of protein localization to lysosome / maintenance of protein location in mitochondrion / cellular response to decreased oxygen levels ...regulation of tRNA methylation / negative regulation of protein maturation / response to insulin-like growth factor stimulus / mammalian oogenesis stage / regulation of glycogen biosynthetic process / positive regulation of protein localization to endoplasmic reticulum / negative regulation of lymphocyte migration / negative regulation of protein localization to lysosome / maintenance of protein location in mitochondrion / cellular response to decreased oxygen levels / cellular response to rapamycin / regulation of type B pancreatic cell development / AKT-mediated inactivation of FOXO1A / negative regulation of long-chain fatty acid import across plasma membrane / Negative regulation of the PI3K/AKT network / maternal placenta development / establishment of protein localization to mitochondrion / activation-induced cell death of T cells / potassium channel activator activity / AKT phosphorylates targets in the nucleus / negative regulation of fatty acid beta-oxidation / neuron projection organization / regulation of microtubule anchoring at centrosome / negative regulation of type B pancreatic cell development / negative regulation of glycogen (starch) synthase activity / negative regulation of mesenchymal stem cell differentiation / negative regulation of hydrogen peroxide-induced neuron intrinsic apoptotic signaling pathway / cellular response to oxidised low-density lipoprotein particle stimulus / superior temporal gyrus development / negative regulation of cilium assembly / positive regulation of protein localization to cilium / negative regulation of glycogen biosynthetic process / Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA / positive regulation of glucose metabolic process / cellular response to peptide / negative regulation of TORC2 signaling / negative regulation of dopaminergic neuron differentiation / maintenance of cell polarity / positive regulation of TORC2 signaling / positive regulation of protein localization to centrosome / RUNX2 regulates genes involved in cell migration / positive regulation of organ growth / interleukin-18-mediated signaling pathway / response to fluid shear stress / fibroblast migration / positive regulation of cilium assembly / MTOR signalling / positive regulation of sodium ion transport / mammary gland epithelial cell differentiation / response to growth factor / beta-catenin destruction complex / CRMPs in Sema3A signaling / heart valve development / APC truncation mutants have impaired AXIN binding / AXIN missense mutants destabilize the destruction complex / Truncations of AMER1 destabilize the destruction complex / tau-protein kinase / complement receptor mediated signaling pathway / RAB GEFs exchange GTP for GDP on RABs / cellular response to granulocyte macrophage colony-stimulating factor stimulus / regulation of microtubule-based process / negative regulation of leukocyte cell-cell adhesion / phosphatidylinositol-3,4-bisphosphate binding / glycogen biosynthetic process / regulation of protein export from nucleus / peripheral nervous system myelin maintenance / positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / 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 / positive regulation of protein localization to cell surface / Maturation of nucleoprotein / cellular response to interleukin-3 / sphingosine-1-phosphate receptor signaling pathway / positive regulation of endodeoxyribonuclease activity / phosphorylation / Wnt signalosome / response to growth hormone / cell migration involved in sprouting angiogenesis / regulation of long-term synaptic potentiation / negative regulation of TOR signaling / anoikis / negative regulation of protein localization to nucleus / regulation of postsynapse organization / Disassembly of the destruction complex and recruitment of AXIN to the membrane / AKT phosphorylates targets in the cytosol / TORC2 complex binding / positive regulation of fibroblast migration / regulation of myelination / negative regulation of calcineurin-NFAT signaling cascade / regulation of axon extension / Maturation of nucleoprotein / labyrinthine layer blood vessel development / tau-protein kinase activity / response to UV-A / negative regulation of epithelial to mesenchymal transition / response to food
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 ...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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-SMR / RAC-alpha serine/threonine-protein kinase / Glycogen synthase kinase-3 beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsKallan, N.C. / Spencer, K.L. / Blake, J.F. / Xu, R. / Heizer, J. / Bencsik, J.R. / Mitchell, I.S. / Gloor, S.L. / Martinson, M. / Risom, T. ...Kallan, N.C. / Spencer, K.L. / Blake, J.F. / Xu, R. / Heizer, J. / Bencsik, J.R. / Mitchell, I.S. / Gloor, S.L. / Martinson, M. / Risom, T. / Gross, S.D. / Morales, T. / Vigers, G.P.A. / Brandhuber, B.J. / Skelton, N.J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Discovery and SAR of spirochromane Akt inhibitors.
Authors: Kallan, N.C. / Spencer, K.L. / Blake, J.F. / Xu, R. / Heizer, J. / Bencsik, J.R. / Mitchell, I.S. / Gloor, S.L. / Martinson, M. / Risom, T. / Gross, S.D. / Morales, T.H. / Wu, W.I. / Vigers, ...Authors: Kallan, N.C. / Spencer, K.L. / Blake, J.F. / Xu, R. / Heizer, J. / Bencsik, J.R. / Mitchell, I.S. / Gloor, S.L. / Martinson, M. / Risom, T. / Gross, S.D. / Morales, T.H. / Wu, W.I. / Vigers, G.P. / Brandhuber, B.J. / Skelton, N.J.
History
DepositionFeb 1, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 30, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 6, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Source and taxonomy / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / entity / entity_name_com / entity_src_gen / pdbx_entity_src_syn / pdbx_entry_details / pdbx_modification_feature / pdbx_struct_mod_residue / struct_conn / struct_ref / struct_ref_seq / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _entity.pdbx_ec / _entity_src_gen.pdbx_beg_seq_num / _entity_src_gen.pdbx_end_seq_num / _entity_src_gen.pdbx_seq_type / _pdbx_struct_mod_residue.details / _struct_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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
C: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,1473
Polymers40,5902
Non-polymers5571
Water4,270237
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1300 Å2
ΔGint-0 kcal/mol
Surface area15350 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.741, 55.720, 91.019
Angle α, β, γ (deg.)90.00, 101.84, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 39466.969 Da / Num. of mol.: 1 / Fragment: kinase domain / 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 Glycogen synthase kinase-3 beta / GSK-3 beta / Serine/threonine-protein kinase GSK3B


Mass: 1123.220 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
References: UniProt: P49841, tau-protein kinase, non-specific serine/threonine protein kinase
#3: Chemical ChemComp-SMR / N-{(2S)-3-[(3S)-8',9'-dihydro-1H,3'H-spiro[piperidine-3,7'-pyrano[3,2-e]indazol]-1-yl]-2-hydroxypropyl}-N-(2-ethoxyethyl)-2,6-dimethylbenzenesulfonamide


Mass: 556.717 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H40N4O5S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 237 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.61 Å3/Da / Density % sol: 52.93 %
Crystal growTemperature: 293 K / Method: under oil / pH: 7.8
Details: 9.7mg/ml protein, 0.6mM GSK-3 beta peptide, 1mM Mg-AMPPNP, 10mM DTT, 22% PEG 4K, 10% Isopropanol, 0.1M Hepes, pH 7.8, 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: Feb 8, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.9→30 Å / Num. all: 29670 / Num. obs: 29146 / % possible obs: 98.2 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.34 % / Rmerge(I) obs: 0.15 / Rsym value: 0.12 / Net I/σ(I): 11.1
Reflection shellResolution: 1.9→2 Å / Redundancy: 1.8 % / Rmerge(I) obs: 0.42 / Mean I/σ(I) obs: 2.5 / Num. unique all: 2257 / Rsym value: 0.31 / % possible all: 87.9

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Processing

Software
NameVersionClassification
CrystalCleardata collection
MOLREPphasing
REFMAC5.5.0109refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→20.68 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.927 / SU B: 3.614 / SU ML: 0.107 / Cross valid method: THROUGHOUT / ESU R Free: 0.154 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.24299 1479 5.1 %RANDOM
Rwork0.19336 ---
obs0.19594 27656 100 %-
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: 40.551 Å2
Baniso -1Baniso -2Baniso -3
1-0.06 Å20 Å20.37 Å2
2---0.73 Å20 Å2
3---0.82 Å2
Refinement stepCycle: LAST / Resolution: 1.9→20.68 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2683 0 39 237 2959
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0222790
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.471.9853760
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2085325
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.4423.333135
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.42815497
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.9911520
X-RAY DIFFRACTIONr_chiral_restr0.1070.2388
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212121
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_it0.8011.51629
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.50122621
X-RAY DIFFRACTIONr_scbond_it2.26331161
X-RAY DIFFRACTIONr_scangle_it3.7024.51139
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
Rfree0.294 29 -
Rwork0.269 704 -
obs--100 %

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