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- PDB-4gv1: PKB alpha in complex with AZD5363 -

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Basic information

Entry
Database: PDB / ID: 4gv1
TitlePKB alpha in complex with AZD5363
ComponentsRAC-alpha serine/threonine-protein kinase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / protein kinase / 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 / mammalian oogenesis stage / 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 ...glycogen cell differentiation involved in embryonic placenta development / regulation of tRNA methylation / response to insulin-like growth factor stimulus / mammalian oogenesis stage / 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 / maternal placenta development / regulation of type B pancreatic cell development / AKT-mediated inactivation of FOXO1A / Negative regulation of the PI3K/AKT network / negative regulation of long-chain fatty acid import across plasma membrane / establishment of protein localization to mitochondrion / activation-induced cell death of T cells / negative regulation of fatty acid beta-oxidation / regulation of glycogen biosynthetic process / AKT phosphorylates targets in the nucleus / cellular response to oxidised low-density lipoprotein particle stimulus / positive regulation of I-kappaB phosphorylation / negative regulation of cilium assembly / Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA / response to fluid shear stress / RUNX2 regulates genes involved in cell migration / positive regulation of organ growth / interleukin-18-mediated signaling pathway / MTOR signalling / fibroblast migration / positive regulation of sodium ion transport / mammary gland epithelial cell differentiation / negative regulation of endopeptidase activity / negative regulation of protein serine/threonine kinase activity / positive regulation of protein localization to cell surface / RAB GEFs exchange GTP for GDP on RABs / positive regulation of endodeoxyribonuclease activity / protein serine/threonine kinase inhibitor activity / positive regulation of glucose metabolic process / response to growth factor / cellular response to granulocyte macrophage colony-stimulating factor stimulus / negative regulation of leukocyte cell-cell adhesion / phosphatidylinositol-3,4-bisphosphate binding / peripheral nervous system myelin maintenance / sphingosine-1-phosphate receptor signaling pathway / glycogen biosynthetic process / positive regulation of fibroblast migration / cell migration involved in sprouting angiogenesis / response to growth hormone / anoikis / regulation of postsynapse organization / AKT phosphorylates targets in the cytosol / execution phase of apoptosis / labyrinthine layer blood vessel development / response to food / regulation of myelination / response to UV-A / KSRP (KHSRP) binds and destabilizes mRNA / Regulation of TP53 Activity through Association with Co-factors / negative regulation of macroautophagy / CTLA4 inhibitory signaling / negative regulation of cGAS/STING signaling pathway / behavioral response to pain / regulation of neuron projection development / negative regulation of Notch signaling pathway / TOR signaling / negative regulation of release of cytochrome c from mitochondria / apoptotic mitochondrial changes / Constitutive Signaling by AKT1 E17K in Cancer / non-canonical NF-kappaB signal transduction / phosphatidylinositol-3,4,5-trisphosphate binding / CD28 dependent PI3K/Akt signaling / positive regulation of cyclin-dependent protein serine/threonine kinase activity / Regulation of localization of FOXO transcription factors / carbohydrate transport / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / Activation of BAD and translocation to mitochondria / positive regulation of G1/S transition of mitotic cell cycle / positive regulation of fat cell differentiation / positive regulation of blood vessel endothelial cell migration / positive regulation of glycogen biosynthetic process / canonical NF-kappaB signal transduction / cellular response to vascular endothelial growth factor stimulus / positive regulation of lipid biosynthetic process / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / eNOS activation / Cyclin E associated events during G1/S transition / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / regulation of cell migration / Cyclin A:Cdk2-associated events at S phase entry / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / negative regulation of protein ubiquitination / lipopolysaccharide-mediated signaling pathway / cellular response to epidermal growth factor stimulus / cellular response to cadmium ion / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / Regulation of TP53 Activity through Acetylation / positive regulation of TORC1 signaling / regulation of mRNA stability
Similarity search - Function
Protein kinase B alpha, catalytic domain / Protein Kinase B, pleckstrin homology 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. ...Protein kinase B alpha, catalytic domain / Protein Kinase B, pleckstrin homology 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-0XZ / RAC-alpha serine/threonine-protein kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / OTHER / Resolution: 1.49 Å
AuthorsAddie, M. / Ballard, P. / Bird, G. / Buttar, D. / Currie, G. / Davies, B. / Debreczeni, J. / Dry, H. / Dudley, P. / Greenwood, R. ...Addie, M. / Ballard, P. / Bird, G. / Buttar, D. / Currie, G. / Davies, B. / Debreczeni, J. / Dry, H. / Dudley, P. / Greenwood, R. / Hatter, G. / Jestel, A. / Johnson, P.D. / Kettle, J.G. / Lane, C. / Lamont, G. / Leach, A. / Luke, R.W.A. / Ogilvie, D. / Page, K. / Pass, M. / Steinbacher, S. / Steuber, H. / Pearson, S. / Ruston, L.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Discovery of 4-Amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an Orally Bioavailable, Potent Inhibitor of Akt Kinases.
Authors: Addie, M. / Ballard, P. / Buttar, D. / Crafter, C. / Currie, G. / Davies, B.R. / Debreczeni, J. / Dry, H. / Dudley, P. / Greenwood, R. / Johnson, P.D. / Kettle, J.G. / Lane, C. / Lamont, G. ...Authors: Addie, M. / Ballard, P. / Buttar, D. / Crafter, C. / Currie, G. / Davies, B.R. / Debreczeni, J. / Dry, H. / Dudley, P. / Greenwood, R. / Johnson, P.D. / Kettle, J.G. / Lane, C. / Lamont, G. / Leach, A. / Luke, R.W. / Morris, J. / Ogilvie, D. / Page, K. / Pass, M. / Pearson, S. / Ruston, L.
History
DepositionAug 30, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 27, 2013Provider: repository / Type: Initial release
Revision 1.1Mar 27, 2013Group: Database references
Revision 1.2Nov 15, 2017Group: Refinement description / Category: software

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: RAC-alpha serine/threonine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,1916
Polymers39,3941
Non-polymers7975
Water7,080393
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)46.852, 58.556, 150.472
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 RAC-alpha serine/threonine-protein kinase / Protein kinase B / PKB / Protein kinase B alpha / PKB alpha / Proto-oncogene c-Akt / RAC-PK-alpha


Mass: 39393.855 Da / Num. of mol.: 1 / Fragment: kinase domain (UNP residues 144-480)
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: Chemical ChemComp-0XZ / 4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide / Protein kinase B


Mass: 428.915 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H25ClN6O2
#3: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 393 / 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: 2.62 Å3/Da / Density % sol: 53.05 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6.9
Details: alcohol, pH 6.9, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 29, 2007 / Details: dynamically bendable mirror
RadiationMonochromator: LN2-cooled fixed-exit Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.49→54.55 Å / Num. all: 68596 / Num. obs: 68595 / % possible obs: 99.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 6 % / Biso Wilson estimate: 21.956 Å2 / Rmerge(I) obs: 0.077 / Net I/σ(I): 13.28
Reflection shellResolution: 1.49→1.53 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.434 / % possible all: 99.8

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Processing

Software
NameVersionClassification
MOLREPphasing
REFMAC5.2.0005refinement
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: OTHER / Resolution: 1.49→54.55 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.956 / SU B: 1.662 / SU ML: 0.06 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / ESU R: 0.068 / ESU R Free: 0.071 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20978 3428 5 %RANDOM
Rwork0.18096 ---
all0.18243 65127 --
obs0.18243 65127 99.94 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 17.789 Å2
Baniso -1Baniso -2Baniso -3
1-0.56 Å20 Å20 Å2
2---0.72 Å20 Å2
3---0.16 Å2
Refinement stepCycle: LAST / Resolution: 1.49→54.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2696 0 54 393 3143
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0222916
X-RAY DIFFRACTIONr_bond_other_d0.0050.022646
X-RAY DIFFRACTIONr_angle_refined_deg1.3721.9883942
X-RAY DIFFRACTIONr_angle_other_deg0.84536186
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0045358
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.90223.404141
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.0115537
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.6591522
X-RAY DIFFRACTIONr_chiral_restr0.080.2413
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.023202
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02627
X-RAY DIFFRACTIONr_nbd_refined0.1980.2532
X-RAY DIFFRACTIONr_nbd_other0.1860.22594
X-RAY DIFFRACTIONr_nbtor_refined0.1780.21352
X-RAY DIFFRACTIONr_nbtor_other0.0810.21488
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1630.2254
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.140.214
X-RAY DIFFRACTIONr_symmetry_vdw_other0.3230.256
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1880.228
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.92722224
X-RAY DIFFRACTIONr_mcbond_other0.5522688
X-RAY DIFFRACTIONr_mcangle_it2.97132744
X-RAY DIFFRACTIONr_scbond_it5.00141454
X-RAY DIFFRACTIONr_scangle_it6.77661185
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.49→1.529 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.35 250 -
Rwork0.326 4762 -
obs--99.84 %

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