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- PDB-2uzr: A transforming mutation in the pleckstrin homology domain of AKT1... -

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Basic information

Entry
Database: PDB / ID: 2uzr
TitleA transforming mutation in the pleckstrin homology domain of AKT1 in cancer (AKT1-PH_E17K)
ComponentsRAC-alpha serine/threonine-protein kinase
KeywordsTRANSFERASE / GLYCOGEN BIOSYNTHESIS / TRANSLATION REGULATION / NUCLEOTIDE- BINDING / GLYCOGEN METABOLISM / ATP-BINDING / SUGAR TRANSPORT / NUCLEAR PROTEIN / SERINE/THREONINE-PROTEIN KINASE / TRANSPORT / CARBOHYDRATE METABOLISM / KINASE / APOPTOSIS / PHOSPHORYLATION / GLUCOSE METABOLISM
Function / homology
Function and homology information


regulation of tRNA methylation / negative regulation of protein maturation / response to insulin-like growth factor stimulus / mammalian oogenesis stage / 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 / 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 / mammalian oogenesis stage / 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 / maintenance of protein location in mitochondrion / cellular response to decreased oxygen levels / cellular response to rapamycin / 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 / 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 / negative regulation of fatty acid beta-oxidation / negative regulation of hydrogen peroxide-induced neuron intrinsic apoptotic signaling pathway / cellular response to oxidised low-density lipoprotein particle stimulus / negative regulation of cilium assembly / 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 / response to fluid shear stress / fibroblast migration / MTOR signalling / positive regulation of sodium ion transport / mammary gland epithelial cell differentiation / response to growth factor / complement receptor mediated signaling pathway / RAB GEFs exchange GTP for GDP on RABs / cellular response to granulocyte macrophage colony-stimulating factor stimulus / negative regulation of leukocyte cell-cell adhesion / phosphatidylinositol-3,4-bisphosphate binding / glycogen biosynthetic process / peripheral nervous system myelin maintenance / 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 / anoikis / regulation of postsynapse organization / AKT phosphorylates targets in the cytosol / TORC2 complex binding / positive regulation of fibroblast migration / regulation of myelination / labyrinthine layer blood vessel development / 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 / response to food / negative regulation of macroautophagy / Co-inhibition by CTLA4 / 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 / 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 / positive regulation of peptidyl-serine phosphorylation / cellular response to vascular endothelial growth factor stimulus / negative regulation of Notch signaling pathway / CD28 dependent PI3K/Akt signaling / 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 fat cell differentiation / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of G1/S transition of mitotic cell cycle / Mitochondrial unfolded protein response (UPRmt) / positive regulation of glycogen biosynthetic process / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / 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 / 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 / Downregulation of ERBB2:ERBB3 signaling / eNOS activation
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 / 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 / Mainly Beta
Similarity search - Domain/homology
RAC-alpha serine/threonine-protein kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.94 Å
AuthorsCarpten, J.D. / Faber, A.L. / Horn, C. / Donoho, G.P. / Briggs, S.L. / Robbins, C.M. / Hostetter, G. / Boguslawski, S. / Moses, T.Y. / Savage, S. ...Carpten, J.D. / Faber, A.L. / Horn, C. / Donoho, G.P. / Briggs, S.L. / Robbins, C.M. / Hostetter, G. / Boguslawski, S. / Moses, T.Y. / Savage, S. / Uhlik, M. / Lin, A. / Du, J. / Qian, Y.W. / Zeckner, D.J. / Tucker-Kellogg, G. / Touchman, J. / Patel, K. / Mousses, S. / Bittner, M. / Schevitz, R. / Lai, M.H. / Blanchard, K.L. / Thomas, J.E.
CitationJournal: Nature / Year: 2007
Title: A transforming mutation in the pleckstrin homology domain of AKT1 in cancer.
Authors: Carpten, J.D. / Faber, A.L. / Horn, C. / Donoho, G.P. / Briggs, S.L. / Robbins, C.M. / Hostetter, G. / Boguslawski, S. / Moses, T.Y. / Savage, S. / Uhlik, M. / Lin, A. / Du, J. / Qian, Y.W. ...Authors: Carpten, J.D. / Faber, A.L. / Horn, C. / Donoho, G.P. / Briggs, S.L. / Robbins, C.M. / Hostetter, G. / Boguslawski, S. / Moses, T.Y. / Savage, S. / Uhlik, M. / Lin, A. / Du, J. / Qian, Y.W. / Zeckner, D.J. / Tucker-Kellogg, G. / Touchman, J. / Patel, K. / Mousses, S. / Bittner, M. / Schevitz, R. / Lai, M.H. / Blanchard, K.L. / Thomas, J.E.
History
DepositionMay 1, 2007Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 17, 2007Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Sep 19, 2018Group: Data collection / Database references ...Data collection / Database references / Source and taxonomy / Structure summary
Category: citation / entity ...citation / entity / entity_name_com / entity_src_gen / entity_src_nat / struct_ref / struct_ref_seq / struct_ref_seq_dif
Item: _citation.journal_id_ISSN / _citation.page_last ..._citation.journal_id_ISSN / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.title / _entity.pdbx_description / _entity.src_method / _entity_name_com.name
Revision 1.4Oct 16, 2019Group: Data collection / Experimental preparation / Other
Category: exptl_crystal_grow / pdbx_database_status / reflns_shell
Item: _exptl_crystal_grow.method / _pdbx_database_status.status_code_sf ..._exptl_crystal_grow.method / _pdbx_database_status.status_code_sf / _reflns_shell.Rmerge_I_obs / _reflns_shell.meanI_over_sigI_obs
Revision 1.5Dec 13, 2023Group: 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 1.6Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / 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


Theoretical massNumber of molelcules
Total (without water)14,7741
Polymers14,7741
Non-polymers00
Water72140
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)83.886, 32.811, 42.160
Angle α, β, γ (deg.)90.00, 119.11, 90.00
Int Tables number5
Space group name H-MC121

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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: 14773.732 Da / Num. of mol.: 1 / Fragment: RESIDUES 1-123 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AKT1, PKB, RAC / Cell line (production host): HEK293T / Production host: Homo sapiens (human)
References: UniProt: P31749, non-specific serine/threonine protein kinase
#2: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 40 / Source method: isolated from a natural source / Formula: H2O
Compound detailsENGINEERED RESIDUE IN CHAIN A, GLU 17 TO LYS
Has protein modificationY
Sequence detailsMUTATED E17K

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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: 1.7 Å3/Da / Density % sol: 28.27 %
Crystal growMethod: vapor diffusion, hanging drop / pH: 7.5
Details: 0.1 M HEPES PH 7.5 AND 1.4 M SODIUM CITRATE, OR 0.1 M SODIUM ACETATE PH 4.6, 0.2 M AMMONIUM ACETATE AND 15%-30% PEG 3350,

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1
DetectorType: ADSC CCD / Detector: CCD / Date: Jul 17, 2006 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.94→36.64 Å / Num. obs: 7529 / % possible obs: 97.1 % / Observed criterion σ(I): 2 / Redundancy: 4 % / Rmerge(I) obs: 0.06 / Net I/σ(I): 4.9
Reflection shellResolution: 1.95→2.02 Å / Redundancy: 2 % / Rmerge(I) obs: 0.139 / Mean I/σ(I) obs: 2.11 / % possible all: 86.4

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1UNQ

1unq


Resolution: 1.94→36.64 Å / Cor.coef. Fo:Fc: 0.928 / Cor.coef. Fo:Fc free: 0.915 / SU B: 4.931 / SU ML: 0.146 / Cross valid method: THROUGHOUT / ESU R: 0.276 / ESU R Free: 0.194 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. RESIDUES 43-47 ARE DISORDERED.
RfactorNum. reflection% reflectionSelection details
Rfree0.257 367 5 %RANDOM
Rwork0.238 ---
obs0.239 6956 97.1 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 30.96 Å2
Baniso -1Baniso -2Baniso -3
1--0.12 Å20 Å20.02 Å2
2--0.17 Å20 Å2
3----0.02 Å2
Refinement stepCycle: LAST / Resolution: 1.94→36.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms956 0 0 40 996
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.022980
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg0.8771.9411323
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.0065111
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.35923.26952
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.21515181
X-RAY DIFFRACTIONr_dihedral_angle_4_deg7.5271510
X-RAY DIFFRACTIONr_chiral_restr0.0690.2139
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.02744
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.1830.2377
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.30.2651
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.3750.259
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1970.264
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1320.219
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.4581.5583
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.812920
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it0.6743460
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it1.0984.5403
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.94→2 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.316 25
Rwork0.275 414

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