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- PDB-8fe2: Structure of J-PKAc chimera complexed with Aplithianine A -

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Basic information

Entry
Database: PDB / ID: 8fe2
TitleStructure of J-PKAc chimera complexed with Aplithianine A
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


cAMP/PKA signal transduction / PKA-mediated phosphorylation of CREB / PKA-mediated phosphorylation of key metabolic factors / ROBO receptors bind AKAP5 / channel activator activity / sperm head / negative regulation of inclusion body assembly / HDL assembly / negative regulation of cAMP/PKA signal transduction / Regulation of glycolysis by fructose 2,6-bisphosphate metabolism ...cAMP/PKA signal transduction / PKA-mediated phosphorylation of CREB / PKA-mediated phosphorylation of key metabolic factors / ROBO receptors bind AKAP5 / channel activator activity / sperm head / negative regulation of inclusion body assembly / HDL assembly / negative regulation of cAMP/PKA signal transduction / Regulation of glycolysis by fructose 2,6-bisphosphate metabolism / mitochondrial protein catabolic process / negative regulation of cAMP-dependent protein kinase activity / nucleotide-activated protein kinase complex / cell communication by electrical coupling involved in cardiac conduction / high-density lipoprotein particle assembly / Rap1 signalling / renal water homeostasis / regulation of protein processing / positive regulation of ATP-dependent activity / protein localization to lipid droplet / transcription regulator inhibitor activity / regulation of bicellular tight junction assembly / cellular response to parathyroid hormone stimulus / cAMP-dependent protein kinase inhibitor activity / cAMP-dependent protein kinase / cellular response to cold / Loss of phosphorylation of MECP2 at T308 / regulation of osteoblast differentiation / CREB1 phosphorylation through the activation of Adenylate Cyclase / PKA activation / sperm capacitation / cAMP-dependent protein kinase activity / ciliary base / negative regulation of glycolytic process through fructose-6-phosphate / cAMP-dependent protein kinase complex / AMP-activated protein kinase activity / negative regulation of protein import into nucleus / negative regulation of interleukin-2 production / postsynaptic modulation of chemical synaptic transmission / cellular response to glucagon stimulus / Triglyceride catabolism / protein kinase A regulatory subunit binding / plasma membrane raft / protein kinase A catalytic subunit binding / PKA activation in glucagon signalling / ATPase activator activity / Regulation of MECP2 expression and activity / chaperone cofactor-dependent protein refolding / mesoderm formation / HSF1-dependent transactivation / RET signaling / DARPP-32 events / response to unfolded protein / Interleukin-3, Interleukin-5 and GM-CSF signaling / regulation of cardiac muscle contraction / Regulation of HSF1-mediated heat shock response / regulation of cardiac conduction / sperm flagellum / Attenuation phase / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / regulation of macroautophagy / Hedgehog 'off' state / regulation of proteasomal protein catabolic process / regulation of cellular response to heat / negative regulation of smoothened signaling pathway / Ion homeostasis / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / forebrain development / Recruitment of mitotic centrosome proteins and complexes / positive regulation of gluconeogenesis / sperm midpiece / protein folding chaperone / negative regulation of TORC1 signaling / Recruitment of NuMA to mitotic centrosomes / calcium channel complex / Anchoring of the basal body to the plasma membrane / Mitochondrial protein degradation / cellular response to epinephrine stimulus / regulation of G2/M transition of mitotic cell cycle / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / protein kinase A signaling / Hsp70 protein binding / protein serine/threonine/tyrosine kinase activity / positive regulation of calcium-mediated signaling / protein export from nucleus / regulation of heart rate / CD209 (DC-SIGN) signaling / AURKA Activation by TPX2 / FCGR3A-mediated IL10 synthesis / acrosomal vesicle / positive regulation of protein export from nucleus / neural tube closure / Regulation of insulin secretion / cellular response to glucose stimulus / Degradation of GLI1 by the proteasome / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / MAPK6/MAPK4 signaling / neuromuscular junction
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-XTI / 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: 2.34 Å
AuthorsDu, L. / Wilson, B.A.P. / Li, N. / Dalilian, M. / Wang, D. / Martinez Fiesco, J.A. / 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
CitationJournal: 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.
History
DepositionDec 5, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 18, 2023Provider: repository / Type: Initial release
Revision 1.1May 1, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name

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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
B: DnaJ homolog subfamily B member 1, 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)100,2356
Polymers99,6374
Non-polymers5992
Water73941
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)50,1183
Polymers49,8182
Non-polymers2991
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1880 Å2
ΔGint-4 kcal/mol
Surface area20710 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)50,1183
Polymers49,8182
Non-polymers2991
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1960 Å2
ΔGint-1 kcal/mol
Surface area20260 Å2
MethodPISA
Unit cell
Length a, b, c (Å)50.633, 171.782, 61.481
Angle α, β, γ (deg.)90.000, 90.070, 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 protein 40


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 BL21(DE3) (bacteria) / Variant (production host): Star
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-XTI / 6-[(6M)-6-(1-methyl-1H-imidazol-5-yl)-2,3-dihydro-4H-1,4-thiazin-4-yl]-9H-purine / Aplithianine A


Mass: 299.354 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C13H13N7S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 41 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.68 Å3/Da / Density % sol: 54.16 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 200 mM Lithium sulfate, 100 mM HEPES 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: Sep 18, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.34→43.62 Å / Num. obs: 43344 / % possible obs: 98.49 % / Redundancy: 3.5 % / Biso Wilson estimate: 51.04 Å2 / CC1/2: 0.999 / CC star: 1 / Rmerge(I) obs: 0.045 / Rpim(I) all: 0.028 / Net I/σ(I): 17.59
Reflection shellResolution: 2.342→2.426 Å / Redundancy: 3.5 % / Rmerge(I) obs: 0.42 / Mean I/σ(I) obs: 3.54 / Num. unique obs: 4243 / CC1/2: 0.83 / CC star: 0.952 / Rpim(I) all: 0.26 / % possible all: 96.7

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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: 2.34→43.62 Å / SU ML: 0.3406 / Cross valid method: FREE R-VALUE / σ(F): 1.38 / Phase error: 27.0539
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2508 3873 4.59 %
Rwork0.1964 80488 -
obs0.1989 43342 96.84 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 58.26 Å2
Refinement stepCycle: LAST / Resolution: 2.34→43.62 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6974 0 42 41 7057
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00817194
X-RAY DIFFRACTIONf_angle_d0.95859703
X-RAY DIFFRACTIONf_chiral_restr0.0511993
X-RAY DIFFRACTIONf_plane_restr0.00811244
X-RAY DIFFRACTIONf_dihedral_angle_d9.8721965
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.34-2.370.30671260.28472640X-RAY DIFFRACTION89.51
2.37-2.40.33441420.2592865X-RAY DIFFRACTION96.53
2.4-2.430.34481220.25582840X-RAY DIFFRACTION95.89
2.43-2.470.31051330.25942849X-RAY DIFFRACTION95.7
2.47-2.50.30121350.25752789X-RAY DIFFRACTION95.24
2.5-2.540.33581390.25792845X-RAY DIFFRACTION94.16
2.54-2.580.34981270.2632698X-RAY DIFFRACTION90.69
2.58-2.620.26381400.26462782X-RAY DIFFRACTION96.95
2.62-2.670.29561440.25993099X-RAY DIFFRACTION99.69
2.67-2.710.41641500.26122898X-RAY DIFFRACTION99.48
2.71-2.770.39441440.2482941X-RAY DIFFRACTION99.61
2.77-2.820.29951430.24253049X-RAY DIFFRACTION99.78
2.82-2.880.28811360.23312856X-RAY DIFFRACTION99.5
2.88-2.950.32241510.21913016X-RAY DIFFRACTION99.34
2.95-3.020.26191500.23182876X-RAY DIFFRACTION98.95
3.02-3.110.27281360.21352949X-RAY DIFFRACTION98.85
3.11-3.20.29031400.23752938X-RAY DIFFRACTION97.84
3.2-3.30.24171440.23012838X-RAY DIFFRACTION96.44
3.3-3.420.30751430.22392829X-RAY DIFFRACTION95.87
3.42-3.560.28621300.2012769X-RAY DIFFRACTION94.25
3.56-3.720.25851280.19452778X-RAY DIFFRACTION92.49
3.72-3.910.24291400.18562838X-RAY DIFFRACTION95.45
3.91-4.160.23831430.17172949X-RAY DIFFRACTION99.26
4.16-4.480.1951380.1552919X-RAY DIFFRACTION99.38
4.48-4.930.18491390.15472975X-RAY DIFFRACTION99.01
4.93-5.640.22291390.16742949X-RAY DIFFRACTION98.88
5.64-7.10.23741300.18792803X-RAY DIFFRACTION95.26
7.1-43.620.18191410.14882911X-RAY DIFFRACTION97.6

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