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- PDB-6s9x: Crystal Structure of AKT1 in Complex with Covalent-Allosteric AKT... -

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Basic information

Entry
Database: PDB / ID: 6s9x
TitleCrystal Structure of AKT1 in Complex with Covalent-Allosteric AKT Inhibitor 15c
ComponentsRAC-alpha serine/threonine-protein kinase
KeywordsTRANSFERASE / Akt1 / Akt2 / Akt3 / borussertib / covalent-allosteric
Function / homology
Function and homology information


regulation of tRNA methylation / negative regulation of protein maturation / mammalian oogenesis stage / 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 ...regulation of tRNA methylation / negative regulation of protein maturation / mammalian oogenesis stage / 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 / : / 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 / cellular response to peptide / positive regulation of TORC2 signaling / positive regulation of glucose metabolic process / RUNX2 regulates genes involved in cell migration / positive regulation of organ growth / mammary gland epithelial cell differentiation / positive regulation of sodium ion transport / interleukin-18-mediated signaling pathway / MTOR signalling / fibroblast migration / response to growth factor / response to fluid shear stress / cellular response to granulocyte macrophage colony-stimulating factor stimulus / RAB GEFs exchange GTP for GDP on RABs / negative regulation of leukocyte cell-cell adhesion / glycogen biosynthetic process / peripheral nervous system myelin maintenance / phosphatidylinositol-3,4-bisphosphate binding / complement receptor mediated signaling pathway / positive regulation of protein localization to cell surface / phosphorylation / sphingosine-1-phosphate receptor signaling pathway / cell migration involved in sprouting angiogenesis / response to growth hormone / anoikis / regulation of postsynapse organization / AKT phosphorylates targets in the cytosol / positive regulation of endodeoxyribonuclease activity / positive regulation of fibroblast migration / regulation of myelination / labyrinthine layer blood vessel development / Regulation of TP53 Activity through Association with Co-factors / execution phase of apoptosis / TORC2 complex binding / KSRP (KHSRP) binds and destabilizes mRNA / response to UV-A / response to food / Mechanical load activates signaling by PIEZO1 and integrins in osteocytes / Co-inhibition by CTLA4 / negative regulation of macroautophagy / cellular response to stress / negative regulation of cGAS/STING signaling pathway / negative regulation of release of cytochrome c from mitochondria / peptidyl-threonine phosphorylation / regulation of neuron projection development / Constitutive Signaling by AKT1 E17K in Cancer / negative regulation of PERK-mediated unfolded protein response / phosphatidylinositol-3,4,5-trisphosphate binding / positive regulation of protein metabolic process / apoptotic mitochondrial changes / behavioral response to pain / TOR signaling / Regulation of localization of FOXO transcription factors / positive regulation of blood vessel endothelial cell migration / cellular response to vascular endothelial growth factor stimulus / CD28 dependent PI3K/Akt signaling / positive regulation of peptidyl-serine phosphorylation / negative regulation of Notch signaling pathway / Activation of BAD and translocation to mitochondria / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of glycogen biosynthetic process / positive regulation of G1/S transition of mitotic cell cycle / protein serine/threonine kinase inhibitor activity / Mitochondrial unfolded protein response (UPRmt) / positive regulation of fat cell differentiation / response to insulin-like growth factor stimulus / 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 / vascular endothelial cell response to laminar fluid shear stress / Cyclin A:Cdk2-associated events at S phase entry / Regulation of TP53 Activity through Acetylation / T cell costimulation / nitric oxide metabolic process
Similarity search - Function
Protein kinase B alpha, catalytic domain / Protein Kinase B, pleckstrin homology domain / Protein kinase, C-terminal / Protein kinase C terminal domain / Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB) / PH-domain like / Extension to Ser/Thr-type protein kinases / PH domain / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. ...Protein kinase B alpha, catalytic domain / Protein Kinase B, pleckstrin homology domain / Protein kinase, C-terminal / Protein kinase C terminal domain / Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB) / PH-domain like / Extension to Ser/Thr-type protein kinases / PH domain / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / PH-like domain superfamily / Roll / 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 Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-L1W / RAC-alpha serine/threonine-protein kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsLandel, I. / Mueller, M.P. / Rauh, D.
Funding support Germany, 3items
OrganizationGrant numberCountry
German Federal Ministry for Education and ResearchBMBF 01GS08104 Germany
German Federal Ministry for Education and Research01ZX1303C Germany
European Regional Development FundEFRE-800400 Germany
CitationJournal: Angew.Chem.Int.Ed.Engl. / Year: 2019
Title: Covalent-Allosteric Inhibitors to Achieve Akt Isoform-Selectivity.
Authors: Quambusch, L. / Landel, I. / Depta, L. / Weisner, J. / Uhlenbrock, N. / Muller, M.P. / Glanemann, F. / Althoff, K. / Siveke, J.T. / Rauh, D.
History
DepositionJul 15, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 16, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 25, 2019Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Oct 1, 2025Group: Advisory / Derived calculations / Structure summary
Category: pdbx_entry_details / pdbx_modification_feature ...pdbx_entry_details / pdbx_modification_feature / pdbx_validate_close_contact / struct_conn / struct_conn_type
Item: _pdbx_entry_details.has_protein_modification

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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)52,4012
Polymers51,7461
Non-polymers6551
Water21612
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area19280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.460, 71.330, 91.560
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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: 51746.035 Da / Num. of mol.: 1
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-L1W / ~{N}-[3-[1-[[4-[5-[(4-hydroxyphenyl)methyl]-6-oxidanylidene-2-phenyl-1~{H}-pyrazin-3-yl]phenyl]methyl]piperidin-4-yl]-2-oxidanylidene-1~{H}-benzimidazol-5-yl]propanamide


Mass: 654.757 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C39H38N6O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 12 / Source method: isolated from a natural source / Formula: H2O
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: 2.24 Å3/Da / Density % sol: 45.04 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 1.25 mM Na-acetate, 3.75 mM Na-citrate, 15% v/v PEG 2000 MME, pH 7.5, 3 mg/mL Akt1 (in 25 mM TRIS, 100 mM NaCl, 10% v/v Glycerol, 5 mM DTT, pH 7.5), 1 uL reservoir + 1 uL protein solution

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.91955 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 4, 2019
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91955 Å / Relative weight: 1
ReflectionResolution: 2.6→45.78 Å / Num. obs: 14741 / % possible obs: 100 % / Redundancy: 13 % / CC1/2: 1 / Rmerge(I) obs: 0.049 / Rrim(I) all: 0.051 / Net I/σ(I): 30.05
Reflection shellResolution: 2.6→2.7 Å / Redundancy: 13.8 % / Rmerge(I) obs: 1.508 / Mean I/σ(I) obs: 1.8 / Num. unique obs: 1558 / CC1/2: 0.764 / Rrim(I) all: 1.566 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.14_3260refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6HHG

6hhg


Resolution: 2.6→38.528 Å / SU ML: 0.44 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 29.76
RfactorNum. reflection% reflection
Rfree0.2343 736 5 %
Rwork0.2128 --
obs0.214 14732 99.95 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 191.97 Å2 / Biso mean: 99.2954 Å2 / Biso min: 50.72 Å2
Refinement stepCycle: final / Resolution: 2.6→38.528 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3162 0 49 12 3223
Biso mean--83.54 89.33 -
Num. residues----382
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork
2.6-2.80070.38491430.36092739
2.8007-3.08250.30281450.27162765
3.0825-3.52830.30351460.25312771
3.5283-4.44420.20891470.19592790
4.4442-38.5280.20791550.19152931
Refinement TLS params.Method: refined / Origin x: 6.0272 Å / Origin y: 3.9021 Å / Origin z: 7.2087 Å
111213212223313233
T0.7066 Å20.0609 Å20.0462 Å2-0.5832 Å20.0612 Å2--0.6174 Å2
L2.4885 °2-0.6194 °20.0909 °2-2.8828 °2-0.7432 °2--2.8284 °2
S-0.1749 Å °-0.0052 Å °-0.1088 Å °-0.1569 Å °-0.0116 Å °-0.0048 Å °0.1126 Å °0.1669 Å °0.1783 Å °
Refinement TLS groupSelection details: (chain A)

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