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- PDB-8uw2: Structure of AKT1(E17K) with compound 3 (zinc-free) -

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Basic information

Entry
Database: PDB / ID: 8uw2
TitleStructure of AKT1(E17K) with compound 3 (zinc-free)
Components
  • NB41
  • RAC-alpha serine/threonine-protein kinase
KeywordsTRANSFERASE/INHIBITOR / Inhibitor / Kinase / TRANSFERASE / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


regulation of tRNA methylation / negative regulation of protein maturation / mammalian oogenesis stage / response to insulin-like growth factor stimulus / negative regulation of fatty acid beta-oxidation / 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 / cellular response to decreased oxygen levels ...regulation of tRNA methylation / negative regulation of protein maturation / mammalian oogenesis stage / response to insulin-like growth factor stimulus / negative regulation of fatty acid beta-oxidation / 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 / cellular response to decreased oxygen levels / cellular response to rapamycin / maintenance of protein location in mitochondrion / AKT-mediated inactivation of FOXO1A / negative regulation of long-chain fatty acid import across plasma membrane / Negative regulation of the PI3K/AKT network / regulation of type B pancreatic cell development / 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 / cellular response to oxidised low-density lipoprotein particle stimulus / negative regulation of cilium assembly / negative regulation of hydrogen peroxide-induced neuron intrinsic apoptotic signaling pathway / Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA / positive regulation of glucose metabolic process / cellular response to peptide / positive regulation of TORC2 signaling / RUNX2 regulates genes involved in cell migration / positive regulation of organ growth / interleukin-18-mediated signaling pathway / mammary gland epithelial cell differentiation / positive regulation of sodium ion transport / MTOR signalling / fibroblast migration / response to fluid shear stress / response to growth factor / cellular response to granulocyte macrophage colony-stimulating factor stimulus / RAB GEFs exchange GTP for GDP on RABs / complement receptor mediated signaling pathway / negative regulation of leukocyte cell-cell adhesion / glycogen biosynthetic process / peripheral nervous system myelin maintenance / phosphatidylinositol-3,4-bisphosphate binding / positive regulation of protein localization to cell surface / positive regulation of endodeoxyribonuclease activity / sphingosine-1-phosphate receptor signaling pathway / phosphorylation / cell migration involved in sprouting angiogenesis / response to growth hormone / regulation of postsynapse organization / anoikis / AKT phosphorylates targets in the cytosol / TORC2 complex binding / positive regulation of fibroblast migration / labyrinthine layer blood vessel development / regulation of myelination / Regulation of TP53 Activity through Association with Co-factors / response to UV-A / execution phase of apoptosis / KSRP (KHSRP) binds and destabilizes mRNA / Mechanical load activates signaling by PIEZO1 and integrins in osteocytes / response to food / Co-inhibition by CTLA4 / negative regulation of cGAS/STING signaling pathway / negative regulation of macroautophagy / cellular response to stress / negative regulation of release of cytochrome c from mitochondria / regulation of neuron projection development / Constitutive Signaling by AKT1 E17K in Cancer / negative regulation of PERK-mediated unfolded protein response / positive regulation of protein metabolic process / apoptotic mitochondrial changes / phosphatidylinositol-3,4,5-trisphosphate binding / TOR signaling / behavioral response to pain / Regulation of localization of FOXO transcription factors / peptidyl-threonine phosphorylation / protein serine/threonine kinase inhibitor activity / cellular response to vascular endothelial growth factor stimulus / negative regulation of Notch signaling pathway / CD28 dependent PI3K/Akt signaling / positive regulation of peptidyl-serine phosphorylation / positive regulation of blood vessel endothelial cell migration / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / Activation of BAD and translocation to mitochondria / positive regulation of glycogen biosynthetic process / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / Mitochondrial unfolded protein response (UPRmt) / positive regulation of G1/S transition of mitotic cell cycle / positive regulation of fat cell differentiation / vascular endothelial cell response to laminar fluid shear stress / positive regulation of lipid biosynthetic process / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / Cyclin E associated events during G1/S transition / Cyclin A:Cdk2-associated events at S phase entry / T cell costimulation / nitric oxide metabolic process / Regulation of TP53 Activity through Acetylation
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 / 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
Similarity search - Domain/homology
: / RAC-alpha serine/threonine-protein kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
Lama glama (llama)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsCraven, G.B. / Taunton, J.
Funding support United States, 1items
OrganizationGrant numberCountry
Tobacco-Related Disease Research Program (TRDRP)T32FT4880 United States
CitationJournal: Nature / Year: 2025
Title: Mutant-selective AKT inhibition through lysine targeting and neo-zinc chelation.
Authors: Craven, G.B. / Chu, H. / Sun, J.D. / Carelli, J.D. / Coyne, B. / Chen, H. / Chen, Y. / Ma, X. / Das, S. / Kong, W. / Zajdlik, A.D. / Yang, K.S. / Reisberg, S.H. / Thompson, P.A. / Lipford, J.R. / Taunton, J.
History
DepositionNov 5, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 4, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification
Revision 1.2Nov 20, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.3Jan 8, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: RAC-alpha serine/threonine-protein kinase
B: NB41
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,30711
Polymers65,0662
Non-polymers1,2419
Water1,910106
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)76.008, 87.632, 197.246
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Space group name HallC2c2
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y,-z+1/2
#4: -x,-y,z+1/2
#5: x+1/2,y+1/2,z
#6: x+1/2,-y+1/2,-z
#7: -x+1/2,y+1/2,-z+1/2
#8: -x+1/2,-y+1/2,z+1/2

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Components

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Protein / Antibody , 2 types, 2 molecules AB

#1: Protein RAC-alpha serine/threonine-protein kinase


Mass: 51153.453 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AKT1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P31749
#2: Antibody NB41


Mass: 13912.609 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli)

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Non-polymers , 4 types, 115 molecules

#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-XOO / 4-{2-[({4-[(2P)-2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}methyl)amino]ethyl}-2-hydroxybenzaldehyde


Mass: 540.614 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H28N6O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 106 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
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: 2.52 Å3/Da / Density % sol: 51.27 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 19% PEG3350, 200 mM Li2SO4, 100 mM BisTris Propane pH 8.5, 10% ethylene glycol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 2.0.1 / Wavelength: 1.0387 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Sep 29, 2022 / Details: Pair of KB mirrors
RadiationMonochromator: DCM Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0387 Å / Relative weight: 1
ReflectionResolution: 2.2→43.82 Å / Num. obs: 33593 / % possible obs: 99.03 % / Redundancy: 2 % / Biso Wilson estimate: 43.29 Å2 / CC1/2: 0.988 / Net I/σ(I): 15.6
Reflection shellResolution: 2.2→2.279 Å / Num. unique obs: 3290 / CC1/2: 0.771

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.2→43.82 Å / SU ML: 0.3189 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 29.0965
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2792 1699 5.06 %
Rwork0.2201 31846 -
obs0.2231 33545 99.04 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 49.83 Å2
Refinement stepCycle: LAST / Resolution: 2.2→43.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4037 0 78 106 4221
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00824281
X-RAY DIFFRACTIONf_angle_d0.95395789
X-RAY DIFFRACTIONf_chiral_restr0.0543610
X-RAY DIFFRACTIONf_plane_restr0.008738
X-RAY DIFFRACTIONf_dihedral_angle_d6.6422612
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2-2.260.30431380.28652603X-RAY DIFFRACTION98.92
2.26-2.340.3261360.27542628X-RAY DIFFRACTION99
2.34-2.420.30281410.25772636X-RAY DIFFRACTION99.14
2.42-2.520.31971300.26522636X-RAY DIFFRACTION98.86
2.52-2.630.34791470.27762628X-RAY DIFFRACTION99.21
2.63-2.770.341440.29082603X-RAY DIFFRACTION98.56
2.77-2.950.36311370.29872610X-RAY DIFFRACTION98.78
2.95-3.170.31171200.26292670X-RAY DIFFRACTION98.76
3.17-3.490.32191480.22642637X-RAY DIFFRACTION98.9
3.49-40.27941500.19522691X-RAY DIFFRACTION99.47
4-5.030.21291610.15582688X-RAY DIFFRACTION99.65
5.04-43.820.23221470.19662816X-RAY DIFFRACTION99.2

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