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- PDB-8fe5: Structure of J-PKAc chimera complexed with Aplithianine B -

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Basic information

Entry
Database: PDB / ID: 8fe5
TitleStructure of J-PKAc chimera complexed with Aplithianine B
Components
  • DnaJ homolog subfamily B member 1,cAMP-dependent protein kinase catalytic subunit alpha
  • cAMP-dependent protein kinase inhibitor alpha
KeywordsSIGNALING PROTEIN / Protein kinase A / Fibrolamellar Hepatocellular Carcinoma / Natural Product
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 / sperm head / HDL assembly / negative regulation of inclusion body assembly / negative regulation of cAMP-dependent protein kinase activity / Regulation of glycolysis by fructose 2,6-bisphosphate metabolism / mitochondrial protein catabolic process ...PKA-mediated phosphorylation of CREB / PKA-mediated phosphorylation of key metabolic factors / ROBO receptors bind AKAP5 / channel activator activity / sperm head / HDL assembly / negative regulation of inclusion body assembly / negative regulation of cAMP-dependent protein kinase activity / Regulation of glycolysis by fructose 2,6-bisphosphate metabolism / mitochondrial protein catabolic process / nucleotide-activated protein kinase complex / cell communication by electrical coupling involved in cardiac conduction / high-density lipoprotein particle assembly / Rap1 signalling / positive regulation of ATP-dependent activity / 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 / Loss of phosphorylation of MECP2 at T308 / cAMP-dependent protein kinase activity / CREB1 phosphorylation through the activation of Adenylate Cyclase / protein localization to lipid droplet / PKA activation / cAMP-dependent protein kinase complex / regulation of bicellular tight junction assembly / cellular response to parathyroid hormone stimulus / negative regulation of interleukin-2 production / negative regulation of protein import into nucleus / cellular response to cold / regulation of osteoblast differentiation / 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 / ATPase activator activity / : / mesoderm formation / cAMP/PKA signal transduction / RET signaling / Regulation of MECP2 expression and activity / sperm flagellum / Interleukin-3, Interleukin-5 and GM-CSF signaling / PKA activation in glucagon signalling / plasma membrane raft / DARPP-32 events / regulation of cardiac conduction / Regulation of HSF1-mediated heat shock response / HSF1-dependent transactivation / response to unfolded protein / regulation of macroautophagy / regulation of cardiac muscle contraction / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / postsynaptic modulation of chemical synaptic transmission / Attenuation phase / vascular endothelial cell response to laminar fluid shear stress / transcription regulator inhibitor activity / renal water homeostasis / Hedgehog 'off' state / regulation of cellular response to heat / forebrain development / 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 / calcium channel complex / Mitochondrial protein degradation / positive regulation of gluconeogenesis / 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 / Hsp70 protein binding / protein serine/threonine/tyrosine kinase activity / protein folding chaperone / 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 / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / 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 / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Degradation of GLI2 by the proteasome
Similarity search - Function
: / HSP40/DnaJ peptide-binding / Chaperone DnaJ, C-terminal / DnaJ C terminal domain / Nt-dnaJ domain signature. / DnaJ domain, conserved site / DnaJ domain / cAMP-dependent protein kinase inhibitor / cAMP-dependent protein kinase inhibitor / DnaJ molecular chaperone homology domain ...: / HSP40/DnaJ peptide-binding / Chaperone DnaJ, C-terminal / DnaJ C terminal domain / Nt-dnaJ domain signature. / DnaJ domain, conserved site / DnaJ domain / cAMP-dependent protein kinase inhibitor / cAMP-dependent protein kinase inhibitor / DnaJ molecular chaperone homology domain / dnaJ domain profile. / Chaperone J-domain superfamily / DnaJ domain / 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
Chem-XTT / cAMP-dependent protein kinase catalytic subunit alpha / DnaJ homolog subfamily B member 1 / cAMP-dependent protein kinase inhibitor alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.51 Å
AuthorsDu, L. / Wilson, B.A.P. / Li, N. / Martinez Fiesco, J.A. / Dalilian, M. / Wang, D. / Smith, E.A. / Wamiru, A. / Goncharova, E.I. / Zhang, P. / O'Keefe, B.R.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
Citation
Journal: J.Nat.Prod. / Year: 2023
Title: Discovery and Synthesis of a Naturally Derived Protein Kinase Inhibitor that Selectively Inhibits Distinct Classes of Serine/Threonine Kinases.
Authors: Du, L. / Wilson, B.A.P. / Li, N. / Shah, R. / Dalilian, M. / Wang, D. / Smith, E.A. / Wamiru, A. / Goncharova, E.I. / Zhang, P. / O'Keefe, B.R.
#1: Journal: To Be Published / Year: 2023
Title: Discovery and Synthesis of a Naturally Derived Protein Kinase Inhibitor that Selectively Inhibits Distinct Classes of Serine/Threonine Kinases
Authors: Wilson, B.A.P. / Li, N. / Martinez Fiesco, J.A. / Dalilian, M. / Wang, D. / Smith, E.A. / Wamiru, A. / Shah, R. / Goncharova, E.I. / Beutler, J.A. / Grkovic, T. / Zhang, P. / O'Keefe, B.R.
History
DepositionDec 5, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 18, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 1, 2023Group: Database references / Category: citation / citation_author
Revision 1.2Nov 8, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3May 1, 2024Group: Database references / Category: citation_author / Item: _citation_author.identifier_ORCID
Revision 1.4Oct 9, 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: DnaJ homolog subfamily B member 1,cAMP-dependent protein kinase catalytic subunit alpha
I: cAMP-dependent protein kinase inhibitor alpha
B: DnaJ homolog subfamily B member 1,cAMP-dependent protein kinase catalytic subunit alpha
J: cAMP-dependent protein kinase inhibitor alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,2676
Polymers99,6374
Non-polymers6312
Water30617
1
A: DnaJ homolog subfamily B member 1,cAMP-dependent protein kinase catalytic subunit alpha
I: cAMP-dependent protein kinase inhibitor alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,1343
Polymers49,8182
Non-polymers3151
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2020 Å2
ΔGint-4 kcal/mol
Surface area21000 Å2
MethodPISA
2
B: DnaJ homolog subfamily B member 1,cAMP-dependent protein kinase catalytic subunit alpha
J: cAMP-dependent protein kinase inhibitor alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,1343
Polymers49,8182
Non-polymers3151
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1950 Å2
ΔGint-5 kcal/mol
Surface area20940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)50.594, 171.715, 62.204
Angle α, β, γ (deg.)90.000, 90.010, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

#1: Protein DnaJ homolog subfamily B member 1,cAMP-dependent protein kinase catalytic subunit alpha / DnaJ protein homolog 1 / Heat shock 40 kDa protein 1 / Heat shock protein 40 / Human DnaJ protein 1 ...DnaJ protein homolog 1 / Heat shock 40 kDa protein 1 / Heat shock protein 40 / Human DnaJ protein 1 / hDj-1 / PKA C-alpha


Mass: 47591.945 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DNAJB1, DNAJ1, HDJ1, HSPF1, PRKACA, PKACA / Production host: Escherichia coli (E. coli)
References: UniProt: P25685, 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-XTT / 6-[(6P)-6-(1-methyl-1H-imidazol-5-yl)-2,3-dihydro-4H-1,4-thiazin-4-yl]-7,9-dihydro-8H-purin-8-one / Aplithianine B


Mass: 315.354 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C13H13N7OS / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 17 / Source method: isolated from a natural source / Formula: H2O
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: 2.71 Å3/Da / Density % sol: 54.64 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 200 mM Lithium Sulfate, 100 mM HEPES 7.5, 25% 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: Jul 30, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.51→43.59 Å / Num. obs: 35478 / % possible obs: 98.26 % / Redundancy: 2 % / Biso Wilson estimate: 52.23 Å2 / CC1/2: 0.999 / CC star: 1 / Rmerge(I) obs: 0.026 / Net I/σ(I): 14.75
Reflection shellResolution: 2.51→2.6 Å / Redundancy: 2 % / Rmerge(I) obs: 0.196 / Mean I/σ(I) obs: 3.47 / Num. unique obs: 3478 / CC1/2: 0.9 / CC star: 0.973 / % possible all: 96.64

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Processing

Software
NameVersionClassification
XDSdata reduction
XDSdata scaling
PHASERphasing
PHENIX1.20.1_4487refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4WB7

4wb7


Resolution: 2.51→43.59 Å / SU ML: 0.3549 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 26.9061
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2432 1999 5.64 %
Rwork0.1901 33468 -
obs0.1931 35467 98.28 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 58.08 Å2
Refinement stepCycle: LAST / Resolution: 2.51→43.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7015 0 44 17 7076
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00897239
X-RAY DIFFRACTIONf_angle_d0.99989765
X-RAY DIFFRACTIONf_chiral_restr0.0528997
X-RAY DIFFRACTIONf_plane_restr0.00811253
X-RAY DIFFRACTIONf_dihedral_angle_d8.1985971
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.51-2.570.3351450.26212314X-RAY DIFFRACTION95.46
2.57-2.640.29061430.23472421X-RAY DIFFRACTION99.73
2.64-2.720.32471440.23782387X-RAY DIFFRACTION99.45
2.72-2.810.33771460.24362426X-RAY DIFFRACTION99.23
2.81-2.910.33711410.25222374X-RAY DIFFRACTION99.41
2.91-3.030.33581480.24732426X-RAY DIFFRACTION99.19
3.03-3.160.31681440.22022358X-RAY DIFFRACTION96.45
3.16-3.330.26381410.22472390X-RAY DIFFRACTION98.83
3.33-3.540.26221390.21542393X-RAY DIFFRACTION99.1
3.54-3.810.24521420.18062411X-RAY DIFFRACTION98.42
3.81-4.20.25281450.17352421X-RAY DIFFRACTION98.39
4.2-4.80.20241370.1572303X-RAY DIFFRACTION95.24
4.8-6.050.2111410.16552416X-RAY DIFFRACTION98.99
6.05-43.590.15151430.15212428X-RAY DIFFRACTION98.02

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