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- PDB-6ccy: Crystal structure of Akt1 in complex with a selective inhibitor -

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Basic information

Entry
Database: PDB / ID: 6ccy
TitleCrystal structure of Akt1 in complex with a selective inhibitor
ComponentsRAC-alpha serine/threonine-protein kinase,PIFtide
KeywordsTRANSFERASE/INHIBITOR / kinase inhibitor / TRANSFERASE / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


glycogen cell differentiation involved in embryonic placenta development / regulation of tRNA methylation / response to insulin-like growth factor stimulus / mammalian oogenesis stage / potassium channel activator activity / epithelial cell migration / negative regulation of protein localization to lysosome / positive regulation of protein localization to endoplasmic reticulum / maintenance of protein location in mitochondrion / negative regulation of lymphocyte migration ...glycogen cell differentiation involved in embryonic placenta development / regulation of tRNA methylation / response to insulin-like growth factor stimulus / mammalian oogenesis stage / potassium channel activator activity / epithelial cell migration / negative regulation of protein localization to lysosome / positive regulation of protein localization to endoplasmic reticulum / maintenance of protein location in mitochondrion / negative regulation of lymphocyte migration / cellular response to decreased oxygen levels / maternal placenta development / regulation of type B pancreatic cell development / AKT-mediated inactivation of FOXO1A / Negative regulation of the PI3K/AKT network / negative regulation of long-chain fatty acid import across plasma membrane / establishment of protein localization to mitochondrion / activation-induced cell death of T cells / negative regulation of fatty acid beta-oxidation / protein kinase C / regulation of glycogen biosynthetic process / AKT phosphorylates targets in the nucleus / cellular response to oxidised low-density lipoprotein particle stimulus / diacylglycerol-dependent serine/threonine kinase activity / positive regulation of I-kappaB phosphorylation / negative regulation of cilium assembly / Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA / response to fluid shear stress / RUNX2 regulates genes involved in cell migration / positive regulation of organ growth / interleukin-18-mediated signaling pathway / MTOR signalling / fibroblast migration / positive regulation of sodium ion transport / cell projection organization / mammary gland epithelial cell differentiation / negative regulation of endopeptidase activity / negative regulation of protein serine/threonine kinase activity / apical junction assembly / positive regulation of protein localization to cell surface / RAB GEFs exchange GTP for GDP on RABs / positive regulation of endodeoxyribonuclease activity / protein serine/threonine kinase inhibitor activity / positive regulation of glucose metabolic process / response to growth factor / cellular response to granulocyte macrophage colony-stimulating factor stimulus / negative regulation of leukocyte cell-cell adhesion / phosphatidylinositol-3,4-bisphosphate binding / peripheral nervous system myelin maintenance / regulation of cell motility / sphingosine-1-phosphate receptor signaling pathway / glycogen biosynthetic process / positive regulation of fibroblast migration / cell migration involved in sprouting angiogenesis / response to growth hormone / anoikis / RNA polymerase binding / regulation of postsynapse organization / intermediate filament cytoskeleton / AKT phosphorylates targets in the cytosol / execution phase of apoptosis / labyrinthine layer blood vessel development / response to food / regulation of myelination / response to UV-A / apical junction complex / KSRP (KHSRP) binds and destabilizes mRNA / Regulation of TP53 Activity through Association with Co-factors / negative regulation of macroautophagy / RHOB GTPase cycle / CTLA4 inhibitory signaling / negative regulation of cGAS/STING signaling pathway / behavioral response to pain / regulation of neuron projection development / negative regulation of Notch signaling pathway / TOR signaling / RHOC GTPase cycle / negative regulation of release of cytochrome c from mitochondria / positive regulation of cytokinesis / apoptotic mitochondrial changes / Constitutive Signaling by AKT1 E17K in Cancer / non-canonical NF-kappaB signal transduction / phosphatidylinositol-3,4,5-trisphosphate binding / cleavage furrow / CD28 dependent PI3K/Akt signaling / positive regulation of cyclin-dependent protein serine/threonine kinase activity / Regulation of localization of FOXO transcription factors / carbohydrate transport / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / RHOA GTPase cycle / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / Activation of BAD and translocation to mitochondria / positive regulation of G1/S transition of mitotic cell cycle / positive regulation of fat cell differentiation / positive regulation of blood vessel endothelial cell migration / positive regulation of glycogen biosynthetic process / canonical NF-kappaB signal transduction / cellular response to vascular endothelial growth factor stimulus / positive regulation of lipid biosynthetic process / positive regulation of viral genome replication
Similarity search - Function
Serine/threonine-protein kinase N, first HR1 domain / Serine/threonine-protein kinase N, C2 domain / Hr1 repeat / Rho effector or protein kinase C-related kinase homology region 1 homologues / HR1 repeat superfamily / Protein kinase B alpha, catalytic domain / Protein Kinase B, pleckstrin homology domain / HR1 rho-binding domain / REM-1 domain profile. / Protein kinase, C-terminal ...Serine/threonine-protein kinase N, first HR1 domain / Serine/threonine-protein kinase N, C2 domain / Hr1 repeat / Rho effector or protein kinase C-related kinase homology region 1 homologues / HR1 repeat superfamily / Protein kinase B alpha, catalytic domain / Protein Kinase B, pleckstrin homology domain / HR1 rho-binding domain / REM-1 domain profile. / Protein kinase, C-terminal / Protein kinase C terminal domain / Protein kinase C conserved region 2 (CalB) / C2 domain / C2 domain profile. / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / PH domain / C2 domain superfamily / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / PH-like domain superfamily / 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 Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-EX4 / RAC-alpha serine/threonine-protein kinase / Serine/threonine-protein kinase N2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.18 Å
AuthorsWang, Y. / Stout, S.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2018
Title: Discovery of chiral dihydropyridopyrimidinones as potent, selective and orally bioavailable inhibitors of AKT.
Authors: Parthasarathy, S. / Henry, K. / Pei, H. / Clayton, J. / Rempala, M. / Johns, D. / De Frutos, O. / Garcia, P. / Mateos, C. / Pleite, S. / Wang, Y. / Stout, S. / Condon, B. / Ashok, S. / Lu, Z. ...Authors: Parthasarathy, S. / Henry, K. / Pei, H. / Clayton, J. / Rempala, M. / Johns, D. / De Frutos, O. / Garcia, P. / Mateos, C. / Pleite, S. / Wang, Y. / Stout, S. / Condon, B. / Ashok, S. / Lu, Z. / Ehlhardt, W. / Raub, T. / Lai, M. / Geeganage, S. / Burkholder, T.P.
History
DepositionFeb 7, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 2, 2018Provider: repository / Type: Initial release
Revision 1.1May 16, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)40,5302
Polymers39,9591
Non-polymers5721
Water1,00956
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)49.664, 66.961, 109.580
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,PIFtide / Protein kinase B / PKB / Protein kinase B alpha / PKB alpha / Proto-oncogene c-Akt / RAC-PK-alpha


Mass: 39958.504 Da / Num. of mol.: 1 / Mutation: N199S, S396P, E397S, T433V
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, UniProt: Q16513, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-EX4 / (5R)-4-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-[2-(pyrrolidin-1-yl)ethyl]-1H-imidazol-2-yl}piperidin-1-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one


Mass: 571.612 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H33F4N7O
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 56 / 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: 2.28 Å3/Da / Density % sol: 46.05 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: 16% PEG 3350 and 200mM Ammonium Formate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.97931 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Feb 3, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97931 Å / Relative weight: 1
ReflectionResolution: 2.18→19.94 Å / Num. obs: 19614 / % possible obs: 99.51 % / Redundancy: 7.2 % / Biso Wilson estimate: 52.25 Å2 / Rmerge(I) obs: 0.576 / Rpim(I) all: 0.34 / Net I/σ(I): 12.1
Reflection shellResolution: 2.18→2.3 Å

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Processing

Software
NameVersionClassification
BUSTER2.11.2refinement
MOSFLM7.0.5data reduction
SCALA3.2.5data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.18→19.94 Å / Cor.coef. Fo:Fc: 0.9282 / Cor.coef. Fo:Fc free: 0.9112 / SU R Cruickshank DPI: 0.29 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.292 / SU Rfree Blow DPI: 0.224 / SU Rfree Cruickshank DPI: 0.225
RfactorNum. reflection% reflectionSelection details
Rfree0.276 1039 5.31 %RANDOM
Rwork0.2352 ---
obs0.2373 19584 99.51 %-
Displacement parametersBiso mean: 58.86 Å2
Baniso -1Baniso -2Baniso -3
1--11.8136 Å20 Å20 Å2
2--2.2487 Å20 Å2
3---9.5649 Å2
Refine analyzeLuzzati coordinate error obs: 0.38 Å
Refinement stepCycle: 1 / Resolution: 2.18→19.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2647 0 41 56 2744
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012767HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.133735HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d989SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes68HARMONIC2
X-RAY DIFFRACTIONt_gen_planes420HARMONIC5
X-RAY DIFFRACTIONt_it2767HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.2
X-RAY DIFFRACTIONt_other_torsion19.88
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion335SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3188SEMIHARMONIC4
LS refinement shellResolution: 2.18→2.3 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.3327 150 5.32 %
Rwork0.2572 2671 -
all0.2611 2821 -
obs--99.51 %

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