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- PDB-3amb: Protein kinase A sixfold mutant model of Aurora B with inhibitor ... -

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Basic information

Entry
Database: PDB / ID: 3amb
TitleProtein kinase A sixfold mutant model of Aurora B with inhibitor VX-680
Components
  • cAMP-dependent protein kinase catalytic subunit alpha
  • cAMP-dependent protein kinase inhibitor alpha
KeywordsTRANSFERASE/TRANSFERASE inhibitor / PKA / protein kinase A / surrogate / VX-680 / MK-0457 / TRANSFERASE-TRANSFERASE inhibitor complex
Function / homology
Function and homology information


PKA-mediated phosphorylation of CREB / PKA-mediated phosphorylation of key metabolic factors / ROBO receptors bind AKAP5 / HDL assembly / channel activator activity / negative regulation of cAMP-dependent protein kinase activity / mitochondrial protein catabolic process / Regulation of glycolysis by fructose 2,6-bisphosphate metabolism / nucleotide-activated protein kinase complex / cell communication by electrical coupling involved in cardiac conduction ...PKA-mediated phosphorylation of CREB / PKA-mediated phosphorylation of key metabolic factors / ROBO receptors bind AKAP5 / HDL assembly / channel activator activity / negative regulation of cAMP-dependent protein kinase activity / mitochondrial protein catabolic process / Regulation of glycolysis by fructose 2,6-bisphosphate metabolism / nucleotide-activated protein kinase complex / cell communication by electrical coupling involved in cardiac conduction / high-density lipoprotein particle assembly / Rap1 signalling / negative regulation of cAMP/PKA signal transduction / cAMP-dependent protein kinase inhibitor activity / cAMP-dependent protein kinase / regulation of protein processing / cAMP-dependent protein kinase activity / protein localization to lipid droplet / cAMP-dependent protein kinase complex / regulation of bicellular tight junction assembly / cellular response to parathyroid hormone stimulus / Loss of phosphorylation of MECP2 at T308 / CREB1 phosphorylation through the activation of Adenylate Cyclase / negative regulation of interleukin-2 production / PKA activation / negative regulation of protein import into nucleus / regulation of osteoblast differentiation / cellular response to cold / sperm capacitation / negative regulation of glycolytic process through fructose-6-phosphate / Triglyceride catabolism / ciliary base / protein kinase A regulatory subunit binding / protein kinase A catalytic subunit binding / intracellular potassium ion homeostasis / mesoderm formation / RET signaling / cAMP/PKA signal transduction / Interleukin-3, Interleukin-5 and GM-CSF signaling / Regulation of MECP2 expression and activity / plasma membrane raft / PKA activation in glucagon signalling / DARPP-32 events / regulation of cardiac conduction / regulation of macroautophagy / regulation of cardiac muscle contraction / sperm flagellum / postsynaptic modulation of chemical synaptic transmission / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / vascular endothelial cell response to laminar fluid shear stress / renal water homeostasis / Hedgehog 'off' state / Ion homeostasis / regulation of G2/M transition of mitotic cell cycle / negative regulation of TORC1 signaling / sperm midpiece / regulation of proteasomal protein catabolic process / cellular response to epinephrine stimulus / calcium channel complex / positive regulation of gluconeogenesis / Mitochondrial protein degradation / protein serine/threonine/tyrosine kinase activity / cellular response to glucagon stimulus / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of mitotic centrosome proteins and complexes / CD209 (DC-SIGN) signaling / acrosomal vesicle / positive regulation of calcium-mediated signaling / Recruitment of NuMA to mitotic centrosomes / regulation of heart rate / Anchoring of the basal body to the plasma membrane / FCGR3A-mediated IL10 synthesis / positive regulation of phagocytosis / protein export from nucleus / AURKA Activation by TPX2 / positive regulation of protein export from nucleus / negative regulation of smoothened signaling pathway / neural tube closure / Regulation of insulin secretion / neuromuscular junction / cellular response to glucose stimulus / Degradation of GLI1 by the proteasome / positive regulation of cholesterol biosynthetic process / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / MAPK6/MAPK4 signaling / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / positive regulation of insulin secretion / peptidyl-serine phosphorylation / VEGFA-VEGFR2 Pathway / mRNA processing / adenylate cyclase-activating G protein-coupled receptor signaling pathway / cytokine-mediated signaling pathway / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / Regulation of PLK1 Activity at G2/M Transition / GPER1 signaling / manganese ion binding
Similarity search - Function
cAMP-dependent protein kinase inhibitor / cAMP-dependent protein kinase inhibitor / cAMP-dependent protein kinase catalytic subunit / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 ...cAMP-dependent protein kinase inhibitor / cAMP-dependent protein kinase inhibitor / cAMP-dependent protein kinase catalytic subunit / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / 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 Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-VX6 / cAMP-dependent protein kinase catalytic subunit alpha / cAMP-dependent protein kinase inhibitor alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.25 Å
AuthorsPflug, A. / de Oliveira, T.M. / Bossemeyer, D. / Engh, R.A.
CitationJournal: Biochem.J. / Year: 2011
Title: Mutants of protein kinase A that mimic the ATP-binding site of Aurora kinase
Authors: Pflug, A. / de Oliveira, T.M. / Bossemeyer, D. / Engh, R.A.
History
DepositionAug 18, 2010Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 3, 2011Provider: repository / Type: Initial release
Revision 1.1Sep 7, 2011Group: Structure summary
Revision 1.2Dec 7, 2011Group: Database references
Revision 1.3Nov 1, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Oct 23, 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

Downloads & links

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Assembly

Deposited unit
A: cAMP-dependent protein kinase catalytic subunit alpha
B: cAMP-dependent protein kinase inhibitor alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,5473
Polymers43,0832
Non-polymers4651
Water1,27971
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1940 Å2
ΔGint-3 kcal/mol
Surface area17550 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.750, 75.240, 80.390
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 cAMP-dependent protein kinase catalytic subunit alpha / PKA / PKA C-alpha


Mass: 40856.469 Da / Num. of mol.: 1 / Mutation: K47R, L95Q, M120L, V123A, Q181K, T183A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PRKACA / Plasmid: pT7-7 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P17612, cAMP-dependent protein kinase
#2: Protein/peptide cAMP-dependent protein kinase inhibitor alpha / PKI / PKI-alpha / cAMP-dependent protein kinase inhibitor / muscle/brain isoform


Mass: 2226.411 Da / Num. of mol.: 1 / Fragment: UNP residues 6-25 / Source method: obtained synthetically / Details: the 5-24 peptide fragment of PKI was synthesized / Source: (synth.) Homo sapiens (human) / References: UniProt: P61925
#3: Chemical ChemComp-VX6 / CYCLOPROPANECARBOXYLIC ACID {4-[4-(4-METHYL-PIPERAZIN-1-YL)-6-(5-METHYL-2H-PYRAZOL-3-YLAMINO)-PYRIMIDIN-2-YLSULFANYL]-PHENYL}-AMIDE


Mass: 464.586 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H28N8OS
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 71 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY
Nonpolymer detailsVX-680 (MK-0457) LABELED AS VX6 WAS PURCHASED FROM SELLECK (SELLECK CHEMICALS LLC, USA).

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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: 2.55 Å3/Da / Density % sol: 51.83 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 25mM Tris-HCl, 25mM NaCl, 1.5mM octanoyl-N-methylglucamide, 1mM (5-24)-PKI, 12-20% (v/v) methanol, 2-methyl-2,4-pentanediol 30%, pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.91841 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Jun 15, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91841 Å / Relative weight: 1
ReflectionResolution: 2.25→37.62 Å / Num. all: 21590 / Num. obs: 21589 / % possible obs: 99.99 % / Redundancy: 4.1 % / Biso Wilson estimate: 25.88 Å2 / Rmerge(I) obs: 0.117 / Rsym value: 0.117 / Net I/σ(I): 5.9
Reflection shellResolution: 2.25→2.37 Å / Redundancy: 4.1 % / Rmerge(I) obs: 0.465 / Mean I/σ(I) obs: 1.6 / Rsym value: 0.465

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Processing

Software
NameVersionClassification
MxCuBEdata collection
MOLREPphasing
REFMAC5.5.0109refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1CDK

1cdk


Resolution: 2.25→36.38 Å / Cor.coef. Fo:Fc: 0.923 / Cor.coef. Fo:Fc free: 0.894 / SU B: 5.885 / SU ML: 0.152 / Cross valid method: THROUGHOUT / ESU R Free: 0.228 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25622 1105 5.1 %RANDOM
Rwork0.21204 ---
obs0.21424 20439 99.99 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 22.909 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0.02 Å20 Å2
3----0.01 Å2
Refinement stepCycle: LAST / Resolution: 2.25→36.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2990 0 33 71 3094
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0223100
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.3061.9674182
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0245360
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.78423.831154
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.86115.054551
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.3991519
X-RAY DIFFRACTIONr_chiral_restr0.0920.2432
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0212354
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.661.51806
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.25622904
X-RAY DIFFRACTIONr_scbond_it1.90631294
X-RAY DIFFRACTIONr_scangle_it3.1214.51275
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.25→2.308 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.276 98 -
Rwork0.223 1474 -
obs--100 %

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