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- PDB-9dc6: Structure of J-PKAc chimera in complex with Aplithianine e1 -

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Basic information

Entry
Database: PDB / ID: 9dc6
TitleStructure of J-PKAc chimera in complex with Aplithianine e1
Components
  • cAMP-dependent protein kinase catalytic subunit alpha
  • cAMP-dependent protein kinase inhibitor alpha
KeywordsTRANSFERASE / Protein kinase A / Fibrolamellar Hepatocellular carcinoma / Natural Product / Signaling protein
Function / homology
Function and homology information


PKA-mediated phosphorylation of CREB / PKA-mediated phosphorylation of key metabolic factors / ROBO receptors bind AKAP5 / channel activator activity / HDL assembly / 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 / channel activator activity / HDL assembly / 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 / intracellular potassium ion homeostasis / 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 / Loss of phosphorylation of MECP2 at T308 / protein localization to lipid droplet / CREB1 phosphorylation through the activation of Adenylate Cyclase / cAMP-dependent protein kinase complex / regulation of bicellular tight junction assembly / cellular response to parathyroid hormone stimulus / PKA activation / negative regulation of interleukin-2 production / negative regulation of protein import into nucleus / regulation of osteoblast differentiation / cellular response to cold / sperm capacitation / ciliary base / negative regulation of glycolytic process through fructose-6-phosphate / Triglyceride catabolism / protein kinase A regulatory subunit binding / protein kinase A catalytic subunit binding / mesoderm formation / RET signaling / cAMP/PKA signal transduction / sperm flagellum / Regulation of MECP2 expression and activity / Interleukin-3, Interleukin-5 and GM-CSF signaling / plasma membrane raft / PKA activation in glucagon signalling / DARPP-32 events / regulation of cardiac conduction / regulation of macroautophagy / regulation of cardiac muscle contraction / 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 / positive regulation of phagocytosis / Ion homeostasis / regulation of G2/M transition of mitotic cell cycle / negative regulation of TORC1 signaling / regulation of proteasomal protein catabolic process / cellular response to epinephrine stimulus / sperm midpiece / positive regulation of gluconeogenesis / Mitochondrial protein degradation / calcium channel complex / CD209 (DC-SIGN) signaling / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / protein serine/threonine/tyrosine kinase activity / Recruitment of mitotic centrosome proteins and complexes / cellular response to glucagon stimulus / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / FCGR3A-mediated IL10 synthesis / positive regulation of calcium-mediated signaling / regulation of heart rate / protein export from nucleus / acrosomal vesicle / AURKA Activation by TPX2 / positive regulation of protein export from nucleus / negative regulation of smoothened signaling pathway / Regulation of insulin secretion / neural tube closure / Degradation of GLI1 by the proteasome / positive regulation of cholesterol biosynthetic process / cellular response to glucose stimulus / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / cytokine-mediated signaling pathway / MAPK6/MAPK4 signaling / neuromuscular junction / positive regulation of insulin secretion / VEGFA-VEGFR2 Pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / mRNA processing / 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 / peptidyl-serine phosphorylation / 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. / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain ...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. / 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
Similarity search - Domain/homology
: / 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: 2.7 Å
AuthorsMartinez Fiesco, J.A. / Zhang, P.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
CitationJournal: J.Med.Chem. / Year: 2025
Title: Chemical Evolution of Aplithianine Class of Serine/Threonine Kinase Inhibitors.
Authors: Du, L. / Wilson, B.A.P. / Moore, W.J. / Dalilian, M. / Shenoy, S.R. / Li, N. / Martinez Fiesco, J.A. / Hwang, J.Y. / Smith, E.A. / Wamiru, A. / Goncharova, E.I. / Alvarez de la Cruz, A. / ...Authors: Du, L. / Wilson, B.A.P. / Moore, W.J. / Dalilian, M. / Shenoy, S.R. / Li, N. / Martinez Fiesco, J.A. / Hwang, J.Y. / Smith, E.A. / Wamiru, A. / Goncharova, E.I. / Alvarez de la Cruz, A. / Pagadala, K. / Piswa, H.K. / Patteti, V. / Jampana, V.P. / Manepalli, P. / Nimmala, R. / Marri, N.R. / Gunuguntla, M. / Reddy, J.J. / Schneekloth Jr., J.S. / Zhang, P. / O'Keefe, B.R.
History
DepositionAug 25, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 9, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)100,0866
Polymers99,4774
Non-polymers6092
Water00
1
A: cAMP-dependent protein kinase catalytic subunit alpha
I: cAMP-dependent protein kinase inhibitor alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,0433
Polymers49,7382
Non-polymers3041
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2220 Å2
ΔGint-3 kcal/mol
Surface area20420 Å2
MethodPISA
2
B: cAMP-dependent protein kinase catalytic subunit alpha
J: cAMP-dependent protein kinase inhibitor alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,0433
Polymers49,7382
Non-polymers3041
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1900 Å2
ΔGint-2 kcal/mol
Surface area20550 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.758, 124.934, 129.302
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein cAMP-dependent protein kinase catalytic subunit alpha / PKA C-alpha


Mass: 47511.969 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PRKACA, PKACA / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Star / References: UniProt: P17612, cAMP-dependent protein kinase
#2: Protein/peptide cAMP-dependent protein kinase inhibitor alpha / PKI-alpha / cAMP-dependent protein kinase inhibitor / muscle/brain isoform


Mass: 2226.411 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P61925
#3: Chemical ChemComp-A1A3I / N-(2-aminoethyl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxamide


Mass: 304.371 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C13H16N6OS / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
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: 2.47 Å3/Da / Density % sol: 50.13 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 200 mM Lithium sulfate, 100 mM Hepes pH 7.5, 20 % PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 23, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.7→41.73 Å / Num. obs: 52108 / % possible obs: 99.67 % / Redundancy: 5.8 % / Biso Wilson estimate: 69.06 Å2 / CC1/2: 0.999 / Net I/σ(I): 14.17
Reflection shellResolution: 2.7→2.86 Å / Num. unique obs: 4371 / CC1/2: 0.964

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Processing

Software
NameVersionClassification
PHENIX1.21.1_5286refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.7→41.73 Å / SU ML: 0.4999 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 33.4771
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.3114 2004 7.24 %
Rwork0.2317 25688 -
obs0.2374 27692 99.67 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 75.35 Å2
Refinement stepCycle: LAST / Resolution: 2.7→41.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7016 0 42 0 7058
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00917236
X-RAY DIFFRACTIONf_angle_d1.09169751
X-RAY DIFFRACTIONf_chiral_restr0.0558997
X-RAY DIFFRACTIONf_plane_restr0.00961268
X-RAY DIFFRACTIONf_dihedral_angle_d19.40572753
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.7-2.770.51191440.44261787X-RAY DIFFRACTION97.33
2.77-2.840.45951320.36311784X-RAY DIFFRACTION99.84
2.84-2.930.41441430.3141807X-RAY DIFFRACTION99.74
2.93-3.020.38651440.30011808X-RAY DIFFRACTION99.69
3.02-3.130.37531370.2851810X-RAY DIFFRACTION99.95
3.13-3.250.39891380.28881814X-RAY DIFFRACTION100
3.25-3.40.3711500.30151840X-RAY DIFFRACTION100
3.4-3.580.4251410.29711826X-RAY DIFFRACTION100
3.58-3.80.29261400.23971827X-RAY DIFFRACTION99.75
3.81-4.10.32221460.22481823X-RAY DIFFRACTION99.85
4.1-4.510.30081420.19611841X-RAY DIFFRACTION99.9
4.51-5.160.24631450.17971867X-RAY DIFFRACTION100
5.16-6.50.27821440.21291881X-RAY DIFFRACTION99.95
6.5-41.730.23561580.17771973X-RAY DIFFRACTION99.39
Refinement TLS params.Method: refined / Origin x: 0.146712187339 Å / Origin y: 0.832478545097 Å / Origin z: 0.14282081629 Å
111213212223313233
T0.390121226417 Å20.0252896707016 Å2-0.0169766961341 Å2-0.337220280897 Å20.0245561887871 Å2--0.334382428266 Å2
L0.158889157863 °20.0195868750213 °2-0.0871649899561 °2-0.0560332470617 °20.396945914387 °2--0.121737332779 °2
S0.04482140727 Å °-0.037841907137 Å °-0.000763447514966 Å °0.0783420193277 Å °0.0500064206382 Å °0.00896368545948 Å °0.138249079848 Å °0.0442170541476 Å °2.53553216332E-6 Å °
Refinement TLS groupSelection details: all

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