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

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Basic information

Entry
Database: PDB / ID: 6hhg
TitleCrystal Structure of AKT1 in Complex with Covalent-Allosteric AKT Inhibitor 27
ComponentsRAC-alpha serine/threonine-protein kinase
KeywordsTRANSFERASE / Akt1 / covalent-allosteric
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 / fibroblast migration / positive regulation of sodium ion transport / MTOR signalling / response to fluid shear stress / response to growth factor / complement receptor mediated signaling pathway / 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 / positive regulation of protein localization to cell surface / sphingosine-1-phosphate receptor signaling pathway / positive regulation of endodeoxyribonuclease activity / 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 / regulation of myelination / labyrinthine layer blood vessel development / 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 macroautophagy / negative regulation of cGAS/STING signaling pathway / 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 / apoptotic mitochondrial changes / positive regulation of protein metabolic process / 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 / Mitochondrial unfolded protein response (UPRmt) / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / 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 / Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB) / PH-domain like / 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 / 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 / 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 / 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-G4T / RAC-alpha serine/threonine-protein kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsLandel, I. / Weisner, J. / Mueller, M.P. / Scheinpflug, R. / Rauh, D.
Funding support Germany, 2items
OrganizationGrant numberCountry
German Federal Ministry for Education and ResearchBMBF 01GS08104 Germany
German Federal Ministry for Education and Research01ZX1303C Germany
CitationJournal: Chem Sci / Year: 2019
Title: Structural and chemical insights into the covalent-allosteric inhibition of the protein kinase Akt.
Authors: Uhlenbrock, N. / Smith, S. / Weisner, J. / Landel, I. / Lindemann, M. / Le, T.A. / Hardick, J. / Gontla, R. / Scheinpflug, R. / Czodrowski, P. / Janning, P. / Depta, L. / Quambusch, L. / ...Authors: Uhlenbrock, N. / Smith, S. / Weisner, J. / Landel, I. / Lindemann, M. / Le, T.A. / Hardick, J. / Gontla, R. / Scheinpflug, R. / Czodrowski, P. / Janning, P. / Depta, L. / Quambusch, L. / Muller, M.P. / Engels, B. / Rauh, D.
History
DepositionAug 28, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 20, 2019Provider: repository / Type: Initial release
Revision 1.1May 1, 2019Group: Data collection / Database references
Category: citation / citation_author ...citation / citation_author / pdbx_database_proc / pdbx_struct_ref_seq_depositor_info
Item: _citation.journal_id_ISSN / _citation.journal_volume ..._citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _pdbx_struct_ref_seq_depositor_info.db_seq_one_letter_code
Revision 1.2Jan 17, 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 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)52,3812
Polymers51,7461
Non-polymers6351
Water1,38777
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 area19240 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.820, 71.230, 91.240
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: 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-G4T / ~{N}-[2-chloranyl-5-[[1-[[4-(5-oxidanylidene-3-phenyl-6~{H}-1,6-naphthyridin-2-yl)phenyl]methyl]piperidin-4-yl]carbamoylamino]phenyl]propanamide


Mass: 635.154 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C36H35ClN6O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 77 / 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: 2.22 Å3/Da / Density % sol: 44.69 %
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 % Glycerol, 5 mM DTT, pH 7.5), 1 uL reservoir + 1 uL protein solution

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99991 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 4, 2017
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99991 Å / Relative weight: 1
ReflectionResolution: 2.3→45.62 Å / Num. obs: 21089 / % possible obs: 99.9 % / Redundancy: 12 % / CC1/2: 0.998 / Rmerge(I) obs: 0.126 / Rrim(I) all: 0.128 / Net I/σ(I): 12.86
Reflection shellResolution: 2.3→2.4 Å / Redundancy: 7.7 % / Rmerge(I) obs: 1.38 / Mean I/σ(I) obs: 1.37 / Num. unique obs: 2459 / CC1/2: 0.599 / Rrim(I) all: 1.46 / % possible all: 99.5

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3O96

3o96


Resolution: 2.3→45.62 Å / SU ML: 0.33 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 28.43
RfactorNum. reflection% reflection
Rfree0.2461 1055 5 %
Rwork0.2104 --
obs0.2121 21088 99.92 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.3→45.62 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3190 0 46 77 3313
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0023319
X-RAY DIFFRACTIONf_angle_d0.5484468
X-RAY DIFFRACTIONf_dihedral_angle_d12.3291270
X-RAY DIFFRACTIONf_chiral_restr0.022464
X-RAY DIFFRACTIONf_plane_restr0.002564
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3-2.40470.36321280.30082434X-RAY DIFFRACTION100
2.4047-2.53150.331300.28142473X-RAY DIFFRACTION100
2.5315-2.69010.33141300.2782468X-RAY DIFFRACTION100
2.6901-2.89770.27421300.25042462X-RAY DIFFRACTION100
2.8977-3.18930.25411310.24682491X-RAY DIFFRACTION100
3.1893-3.65060.27281320.222507X-RAY DIFFRACTION100
3.6506-4.59870.20331340.1682543X-RAY DIFFRACTION100
4.5987-45.6290.21631400.18522655X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 13.6717 Å / Origin y: -11.7036 Å / Origin z: -15.8588 Å
111213212223313233
T0.3039 Å2-0.0136 Å2-0.0346 Å2-0.4016 Å20.0277 Å2--0.3244 Å2
L2.0534 °20.6795 °20.0553 °2-2.4788 °20.1705 °2--2.1141 °2
S-0.0367 Å °0.0455 Å °-0.0731 Å °-0.0174 Å °-0.0908 Å °-0.0442 Å °-0.0501 Å °0.0067 Å °0.1326 Å °
Refinement TLS groupSelection details: (chain A)

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