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- PDB-8uw9: Structure of AKT1(E17K) with compound 4 -

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Basic information

Entry
Database: PDB / ID: 8uw9
TitleStructure of AKT1(E17K) with compound 4
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 / response to insulin-like growth factor stimulus / regulation of glycogen biosynthetic process / negative regulation of protein localization to lysosome / positive regulation of protein localization to endoplasmic reticulum / negative regulation of lymphocyte migration / cellular response to rapamycin / 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 / regulation of glycogen biosynthetic process / negative regulation of protein localization to lysosome / positive regulation of protein localization to endoplasmic reticulum / negative regulation of lymphocyte migration / cellular response to rapamycin / maintenance of protein location in mitochondrion / cellular response to decreased oxygen levels / maternal placenta development / 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 / potassium channel activator activity / establishment of protein localization to mitochondrion / AKT phosphorylates targets in the nucleus / negative regulation of fatty acid beta-oxidation / cellular response to oxidised low-density lipoprotein particle stimulus / negative regulation of hydrogen peroxide-induced neuron intrinsic apoptotic signaling pathway / negative regulation of cilium assembly / cellular response to peptide / Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA / positive regulation of organ growth / positive regulation of TORC2 signaling / RUNX2 regulates genes involved in cell migration / interleukin-18-mediated signaling pathway / response to fluid shear stress / fibroblast migration / MTOR signalling / positive regulation of sodium ion transport / mammary gland epithelial cell differentiation / response to growth factor / positive regulation of glucose metabolic process / cellular response to granulocyte macrophage colony-stimulating factor stimulus / RAB GEFs exchange GTP for GDP on RABs / phosphatidylinositol-3,4-bisphosphate binding / negative regulation of leukocyte cell-cell adhesion / positive regulation of protein localization to cell surface / peripheral nervous system myelin maintenance / glycogen biosynthetic process / sphingosine-1-phosphate receptor signaling pathway / positive regulation of endodeoxyribonuclease activity / response to growth hormone / cell migration involved in sprouting angiogenesis / positive regulation of fibroblast migration / anoikis / protein serine/threonine kinase inhibitor activity / mammalian oogenesis stage / regulation of postsynapse organization / labyrinthine layer blood vessel development / AKT phosphorylates targets in the cytosol / activation-induced cell death of T cells / TORC2 complex binding / regulation of myelination / response to food / response to UV-A / Regulation of TP53 Activity through Association with Co-factors / Mechanical load activates signaling by PIEZO1 and integrins in osteocytes / KSRP (KHSRP) binds and destabilizes mRNA / execution phase of apoptosis / phosphorylation / apoptotic mitochondrial changes / Co-inhibition by CTLA4 / negative regulation of macroautophagy / negative regulation of cGAS/STING signaling pathway / cellular response to stress / regulation of neuron projection development / negative regulation of release of cytochrome c from mitochondria / Constitutive Signaling by AKT1 E17K in Cancer / negative regulation of PERK-mediated unfolded protein response / phosphatidylinositol-3,4,5-trisphosphate binding / behavioral response to pain / TOR signaling / positive regulation of protein metabolic process / Regulation of localization of FOXO transcription factors / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / negative regulation of Notch signaling pathway / cellular response to vascular endothelial growth factor stimulus / CD28 dependent PI3K/Akt signaling / positive regulation of blood vessel endothelial cell migration / Activation of BAD and translocation to mitochondria / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / positive regulation of G1/S transition of mitotic cell cycle / positive regulation of fat cell differentiation / Mitochondrial unfolded protein response (UPRmt) / positive regulation of glycogen biosynthetic process / vascular endothelial cell response to laminar fluid shear stress / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / positive regulation of lipid biosynthetic process / Cyclin E associated events during G1/S transition / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / Cyclin A:Cdk2-associated events at S phase entry / eNOS activation / positive regulation of peptidyl-serine phosphorylation / negative regulation of proteolysis / nitric oxide metabolic process / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / 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: 1.9 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 6, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 4, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 23, 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)66,31012
Polymers65,0662
Non-polymers1,24410
Water2,792155
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)76.215, 87.209, 198.096
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 , 6 types, 165 molecules

#3: Chemical ChemComp-XQ2 / N-({4-[(2P)-2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}methyl)-2-(2-fluoro-4-formyl-3-hydroxyphenyl)acetamide


Mass: 572.588 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H25FN6O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#6: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#7: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 155 / 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: 2.53 Å3/Da / Density % sol: 51.37 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 15% PEG3350, 200 mM Li2SO4, 100 mM BisTris Propane pH 6.5, 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: Jun 24, 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: 1.9→36.39 Å / Num. obs: 52272 / % possible obs: 99.73 % / Redundancy: 2 % / Biso Wilson estimate: 36.13 Å2 / CC1/2: 0.999 / Net I/σ(I): 10.89
Reflection shellResolution: 1.9→1.968 Å / Num. unique obs: 5173 / CC1/2: 0.505

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→36.39 Å / SU ML: 0.2563 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 26.8772
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2448 2608 4.99 %
Rwork0.2046 49650 -
obs0.2067 52258 99.76 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 48.35 Å2
Refinement stepCycle: LAST / Resolution: 1.9→36.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4037 0 76 155 4268
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0084290
X-RAY DIFFRACTIONf_angle_d1.04175795
X-RAY DIFFRACTIONf_chiral_restr0.0607607
X-RAY DIFFRACTIONf_plane_restr0.0081739
X-RAY DIFFRACTIONf_dihedral_angle_d6.9678613
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-1.930.36481590.32442587X-RAY DIFFRACTION99.46
1.93-1.970.36231450.31282555X-RAY DIFFRACTION99.89
1.97-2.010.32151230.28212591X-RAY DIFFRACTION99.34
2.01-2.060.30731370.27542586X-RAY DIFFRACTION99.96
2.06-2.10.31451270.25492587X-RAY DIFFRACTION99.93
2.1-2.160.33061160.25222612X-RAY DIFFRACTION99.78
2.16-2.210.23581360.23442597X-RAY DIFFRACTION100
2.21-2.280.31470.22412577X-RAY DIFFRACTION99.96
2.28-2.350.27321280.22762608X-RAY DIFFRACTION99.89
2.35-2.440.23851340.21772611X-RAY DIFFRACTION99.85
2.44-2.530.28161520.21922586X-RAY DIFFRACTION100
2.53-2.650.27731280.22822623X-RAY DIFFRACTION99.96
2.65-2.790.27641190.21932616X-RAY DIFFRACTION99.67
2.79-2.960.26821470.21662600X-RAY DIFFRACTION99.82
2.96-3.190.29421330.22652629X-RAY DIFFRACTION99.68
3.19-3.510.23281280.19852628X-RAY DIFFRACTION99.78
3.51-4.020.23291360.18282653X-RAY DIFFRACTION99.71
4.02-5.060.19561510.15842637X-RAY DIFFRACTION99.15
5.07-36.390.20371620.18682767X-RAY DIFFRACTION99.63

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