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

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Basic information

Entry
Database: PDB / ID: 6hhh
TitleCrystal Structure of AKT1 in Complex with Covalent-Allosteric AKT Inhibitor 31
ComponentsRAC-alpha serine/threonine-protein kinase
KeywordsTRANSFERASE / Akt1 / covalent-allosteric
Function / homology
Function and homology information


glycogen cell differentiation involved in embryonic placenta development / regulation of tRNA methylation / negative regulation of protein maturation / response to insulin-like growth factor stimulus / potassium channel activator activity / negative regulation of protein localization to lysosome / positive regulation of protein localization to endoplasmic reticulum / negative regulation of lymphocyte migration / maintenance of protein location in mitochondrion / cellular response to rapamycin ...glycogen cell differentiation involved in embryonic placenta development / regulation of tRNA methylation / negative regulation of protein maturation / response to insulin-like growth factor stimulus / potassium channel activator activity / negative regulation of protein localization to lysosome / positive regulation of protein localization to endoplasmic reticulum / negative regulation of lymphocyte migration / maintenance of protein location in mitochondrion / cellular response to rapamycin / cellular response to decreased oxygen levels / regulation of type B pancreatic cell development / AKT-mediated inactivation of FOXO1A / maternal placenta development / Negative regulation of the PI3K/AKT network / negative regulation of long-chain fatty acid import across plasma membrane / establishment of protein localization to mitochondrion / 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 / negative regulation of cilium assembly / positive regulation of I-kappaB phosphorylation / Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA / RUNX2 regulates genes involved in cell migration / positive regulation of organ growth / response to fluid shear stress / cellular response to peptide / negative regulation of endopeptidase activity / interleukin-18-mediated signaling pathway / fibroblast migration / MTOR signalling / positive regulation of sodium ion transport / mammary gland epithelial cell differentiation / negative regulation of protein serine/threonine kinase activity / positive regulation of glucose metabolic process / RAB GEFs exchange GTP for GDP on RABs / response to growth hormone / response to growth factor / cellular response to granulocyte macrophage colony-stimulating factor stimulus / positive regulation of endodeoxyribonuclease activity / negative regulation of leukocyte cell-cell adhesion / phosphatidylinositol-3,4-bisphosphate binding / positive regulation of protein localization to cell surface / peripheral nervous system myelin maintenance / glycogen biosynthetic process / negative regulation of cGAS/STING signaling pathway / sphingosine-1-phosphate receptor signaling pathway / protein serine/threonine kinase inhibitor activity / cell migration involved in sprouting angiogenesis / positive regulation of fibroblast migration / anoikis / AKT phosphorylates targets in the cytosol / non-canonical NF-kappaB signal transduction / response to food / labyrinthine layer blood vessel development / response to UV-A / regulation of myelination / regulation of postsynapse organization / KSRP (KHSRP) binds and destabilizes mRNA / Regulation of TP53 Activity through Association with Co-factors / execution phase of apoptosis / negative regulation of macroautophagy / CTLA4 inhibitory signaling / mammalian oogenesis stage / negative regulation of release of cytochrome c from mitochondria / negative regulation of Notch signaling pathway / activation-induced cell death of T cells / behavioral response to pain / regulation of neuron projection development / Constitutive Signaling by AKT1 E17K in Cancer / phosphatidylinositol-3,4,5-trisphosphate binding / CD28 dependent PI3K/Akt signaling / apoptotic mitochondrial changes / Regulation of localization of FOXO transcription factors / positive regulation of cyclin-dependent protein serine/threonine kinase activity / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of glycogen biosynthetic process / Activation of BAD and translocation to mitochondria / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / positive regulation of blood vessel endothelial cell migration / cellular response to vascular endothelial growth factor stimulus / TOR signaling / positive regulation of fat cell differentiation / positive regulation of G1/S transition of mitotic cell cycle / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / eNOS activation / canonical NF-kappaB signal transduction / Cyclin E associated events during G1/S transition / positive regulation of lipid biosynthetic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / phosphorylation / Cyclin A:Cdk2-associated events at S phase entry / lipopolysaccharide-mediated signaling pathway / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / 14-3-3 protein binding / Regulation of TP53 Activity through Acetylation / negative regulation of protein ubiquitination / striated muscle cell differentiation / positive regulation of endothelial cell proliferation
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 / 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 Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-G4Q / RAC-alpha serine/threonine-protein kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)52,2902
Polymers51,7461
Non-polymers5441
Water37821
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)70.320, 70.890, 91.080
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 / Akt1


Mass: 51746.035 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P31749
#2: Chemical ChemComp-G4Q / ~{N}-[4-[4-[[4-(5-oxidanylidene-3-phenyl-6~{H}-1,6-naphthyridin-2-yl)phenyl]methyl]piperazin-1-yl]phenyl]propanamide


Mass: 543.658 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H33N5O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 21 / 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: 2.19 Å3/Da / Density % sol: 43.93 %
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), 1ul reservoir + 1ul protein solution

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99992 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 16, 2016
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99992 Å / Relative weight: 1
ReflectionResolution: 2.7→45.54 Å / Num. obs: 13005 / % possible obs: 100 % / Redundancy: 13 % / CC1/2: 1 / Rmerge(I) obs: 0.074 / Rrim(I) all: 0.075 / Net I/σ(I): 24.48
Reflection shellResolution: 2.7→2.8 Å / Redundancy: 13.8 % / Rmerge(I) obs: 0.997 / Mean I/σ(I) obs: 2.77 / Num. unique obs: 1303 / CC1/2: 0.921 / Rrim(I) all: 0.997 / % possible all: 99.8

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6HHG

6hhg


Resolution: 2.7→45.54 Å / SU ML: 0.28 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 28.96
RfactorNum. reflection% reflection
Rfree0.2657 651 5.01 %
Rwork0.2144 --
obs0.217 13003 99.97 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.7→45.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3132 0 41 21 3194
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0053254
X-RAY DIFFRACTIONf_angle_d0.7874382
X-RAY DIFFRACTIONf_dihedral_angle_d13.1781245
X-RAY DIFFRACTIONf_chiral_restr0.029454
X-RAY DIFFRACTIONf_plane_restr0.003556
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.7001-2.90860.3381270.26922398X-RAY DIFFRACTION100
2.9086-3.20120.29351290.25092448X-RAY DIFFRACTION100
3.2012-3.66430.29661280.22882435X-RAY DIFFRACTION100
3.6643-4.61590.23621300.1972476X-RAY DIFFRACTION100
4.6159-45.54650.25841370.20582595X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -5.7983 Å / Origin y: 3.3897 Å / Origin z: -7.4617 Å
111213212223313233
T0.471 Å2-0.0638 Å20.0795 Å2-0.3721 Å2-0.0622 Å2--0.3997 Å2
L3.2472 °21.3407 °20.1913 °2-4.9324 °20.6357 °2--3.3412 °2
S-0.1801 Å °0.0041 Å °-0.1641 Å °0.1355 Å °0.0384 Å °0.0052 Å °0.395 Å °-0.1546 Å °0.1049 Å °
Refinement TLS groupSelection details: (chain A)

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