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- EMDB-47946: Reset Type-I Protein Kinase A Holoenzyme -

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Basic information

Entry
Database: EMDB / ID: EMD-47946
TitleReset Type-I Protein Kinase A Holoenzyme
Map data
Sample
  • Complex: Reset type-I PKA holoenzyme complex of regulatory and catalytic subunits
    • Protein or peptide: cAMP-dependent protein kinase catalytic subunit alpha
    • Protein or peptide: cAMP-dependent protein kinase type I-alpha regulatory subunit
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
KeywordsKinase / Regulator / SIGNALING PROTEIN
Function / homology
Function and homology information


PKA-mediated phosphorylation of CREB / PKA-mediated phosphorylation of key metabolic factors / ROBO receptors bind AKAP5 / PKA activation in glucagon signalling / DARPP-32 events / CREB1 phosphorylation through the activation of Adenylate Cyclase / GPER1 signaling / Factors involved in megakaryocyte development and platelet production / HDL assembly / channel activator activity ...PKA-mediated phosphorylation of CREB / PKA-mediated phosphorylation of key metabolic factors / ROBO receptors bind AKAP5 / PKA activation in glucagon signalling / DARPP-32 events / CREB1 phosphorylation through the activation of Adenylate Cyclase / GPER1 signaling / Factors involved in megakaryocyte development and platelet production / HDL assembly / channel activator activity / PKA activation / mitochondrial protein catabolic process / Regulation of glycolysis by fructose 2,6-bisphosphate metabolism / Hedgehog 'off' state / cell communication by electrical coupling involved in cardiac conduction / high-density lipoprotein particle assembly / nucleotide-activated protein kinase complex / potassium channel inhibitor activity / Rap1 signalling / cAMP-dependent protein kinase inhibitor activity / histone H1-4S35 kinase activity / cAMP-dependent protein kinase / regulation of protein processing / cAMP-dependent protein kinase activity / cellular response to parathyroid hormone stimulus / protein localization to lipid droplet / negative regulation of interleukin-2 production / regulation of bicellular tight junction assembly / cAMP-dependent protein kinase complex / sarcomere organization / Loss of phosphorylation of MECP2 at T308 / dorsal/ventral neural tube patterning / CREB1 phosphorylation through the activation of Adenylate Cyclase / PKA activation / sperm head-tail coupling apparatus / regulation of osteoblast differentiation / Triglyceride catabolism / cellular response to cold / sperm capacitation / negative regulation of activated T cell proliferation / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Vasopressin regulates renal water homeostasis via Aquaporins / negative regulation of glycolytic process through fructose-6-phosphate / ciliary base / protein kinase A catalytic subunit binding / protein kinase A regulatory subunit binding / intracellular potassium ion homeostasis / RET signaling / mesoderm formation / Interleukin-3, Interleukin-5 and GM-CSF signaling / immunological synapse / PKA activation in glucagon signalling / plasma membrane raft / Regulation of MECP2 expression and activity / regulation of cardiac conduction / regulation of macroautophagy / DARPP-32 events / cardiac muscle cell proliferation / axoneme / cAMP/PKA signal transduction / regulation of cardiac muscle contraction / sperm flagellum / negative regulation of cAMP/PKA signal transduction / vascular endothelial cell response to laminar fluid shear stress / postsynaptic modulation of chemical synaptic transmission / cAMP binding / renal water homeostasis / Hedgehog 'off' state / Ion homeostasis / multivesicular body / negative regulation of protein localization to chromatin / regulation of proteasomal protein catabolic process / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / negative regulation of TORC1 signaling / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / protein serine/threonine/tyrosine kinase activity / cellular response to epinephrine stimulus / Recruitment of mitotic centrosome proteins and complexes / CD209 (DC-SIGN) signaling / calcium channel complex / cellular response to glucagon stimulus / protein export from nucleus / positive regulation of gluconeogenesis / Recruitment of NuMA to mitotic centrosomes / positive regulation of calcium-mediated signaling / Anchoring of the basal body to the plasma membrane / Mitochondrial protein degradation / acrosomal vesicle / regulation of heart rate / FCGR3A-mediated IL10 synthesis / positive regulation of phagocytosis / AURKA Activation by TPX2 / regulation of microtubule cytoskeleton organization / positive regulation of protein export from nucleus / negative regulation of smoothened signaling pathway / neuromuscular junction / neural tube closure / Regulation of insulin secretion / cellular response to glucose stimulus
Similarity search - Function
cAMP-dependent protein kinase regulatory subunit / cAMP-dependent protein kinase regulatory subunit, dimerization-anchoring domain / Regulatory subunit of type II PKA R-subunit / RIIalpha, Regulatory subunit portion of type II PKA R-subunit / : / Cyclic nucleotide-binding domain signature 2. / Cyclic nucleotide-binding domain signature 1. / cAMP-dependent protein kinase catalytic subunit / Cyclic nucleotide-binding, conserved site / Cyclic nucleotide-monophosphate binding domain ...cAMP-dependent protein kinase regulatory subunit / cAMP-dependent protein kinase regulatory subunit, dimerization-anchoring domain / Regulatory subunit of type II PKA R-subunit / RIIalpha, Regulatory subunit portion of type II PKA R-subunit / : / Cyclic nucleotide-binding domain signature 2. / Cyclic nucleotide-binding domain signature 1. / cAMP-dependent protein kinase catalytic subunit / Cyclic nucleotide-binding, conserved site / Cyclic nucleotide-monophosphate binding domain / Cyclic nucleotide-binding domain / cAMP/cGMP binding motif profile. / Cyclic nucleotide-binding domain / Cyclic nucleotide-binding domain superfamily / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / RmlC-like jelly roll fold / 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 type I-alpha regulatory subunit / cAMP-dependent protein kinase catalytic subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human) / Bos taurus (domestic cattle)
Methodsingle particle reconstruction / cryo EM / Resolution: 5.9 Å
AuthorsVenkatakrishnan V / Buckley T / Laremore TN / Armache JP / Anand GS
Funding support United States, 1 items
OrganizationGrant numberCountry
Not funded United States
CitationJournal: J Am Chem Soc / Year: 2025
Title: Multiplicity of Regulatory Subunit Conformations Defines Structural Ensemble of Reset Protein Kinase A Holoenzyme.
Authors: Varun Venkatakrishnan / Tatiana N Laremore / Theresa S C Buckley / Jean-Paul Armache / Ganesh S Anand /
Abstract: How protein kinase A (PKA) is reset to a basal state following 3'5'-cyclic adenosine monophosphate (cAMP)-mediated activation is unknown. Here we describe the mechanism of cAMP-PKA type I signal ...How protein kinase A (PKA) is reset to a basal state following 3'5'-cyclic adenosine monophosphate (cAMP)-mediated activation is unknown. Here we describe the mechanism of cAMP-PKA type I signal termination leading to a reset of PKA by holoenzyme formation through the obligatory action of phosphodiesterases (PDEs). We report a catalytic subunit (Cα)-assisted mechanism for the reset of type I PKA and describe for the first time multiple structures of the reset PKA holoenzyme (RIα:Cα) that capture an ensemble of multiple conformational end-states through integrative electron microscopy and structural mass spectrometry approaches. Together these complementary methods highlight the large conformational dynamics of the regulatory subunit (RIα) within the tetrameric reset PKA holoenzyme. The cAMP-free reset PKA holoenzyme adopts multiple distinct conformations of RIα with contributions from the N-terminal linker and CNB-B dynamics. Our findings highlight the interplay between RIα, Cα, and PDEs (PDE8) in cAMP-PKA signalosomes to offer a new paradigm for PDE-mediated regulation of cAMP-PKA signaling.
History
DepositionNov 16, 2024-
Header (metadata) releaseApr 23, 2025-
Map releaseApr 23, 2025-
UpdateMay 14, 2025-
Current statusMay 14, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_47946.png

Downloads & links

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Map

FileDownload / File: emd_47946.map.gz / Format: CCP4 / Size: 40.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.94 Å/pix.
x 220 pix.
= 207.68 Å		0.94 Å/pix.
x 220 pix.
= 207.68 Å		0.94 Å/pix.
x 220 pix.
= 207.68 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.944 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.128
Minimum - Maximum-0.5711139 - 1.1862156
Average (Standard dev.)-0.0006724903 (±0.031340785)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions220220220
Spacing220220220
CellA=B=C: 207.68001 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_47946_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_47946_half_map_2.map
Projections & Slices
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Sample components

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Entire : Reset type-I PKA holoenzyme complex of regulatory and catalytic s...

EntireName: Reset type-I PKA holoenzyme complex of regulatory and catalytic subunits
Components
  • Complex: Reset type-I PKA holoenzyme complex of regulatory and catalytic subunits
    • Protein or peptide: cAMP-dependent protein kinase catalytic subunit alpha
    • Protein or peptide: cAMP-dependent protein kinase type I-alpha regulatory subunit
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE

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Supramolecule #1: Reset type-I PKA holoenzyme complex of regulatory and catalytic s...

SupramoleculeName: Reset type-I PKA holoenzyme complex of regulatory and catalytic subunits
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: cAMP-dependent protein kinase catalytic subunit alpha

MacromoleculeName: cAMP-dependent protein kinase catalytic subunit alpha / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: cAMP-dependent protein kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.657316 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: GNAAAAKKGS EQESVKEFLA KAKEDFLKKW ETPSQNTAQL DQFDRIKTLG TGSFGRVMLV KHKESGNHYA MKILDKQKVV KLKQIEHTL NEKRILQAVN FPFLVKLEFS FKDNSNLYMV MEYVAGGEMF SHLRRIGRFS EPHARFYAAQ IVLTFEYLHS L DLIYRDLK ...String:
GNAAAAKKGS EQESVKEFLA KAKEDFLKKW ETPSQNTAQL DQFDRIKTLG TGSFGRVMLV KHKESGNHYA MKILDKQKVV KLKQIEHTL NEKRILQAVN FPFLVKLEFS FKDNSNLYMV MEYVAGGEMF SHLRRIGRFS EPHARFYAAQ IVLTFEYLHS L DLIYRDLK PENLLIDQQG YIQVTDFGFA KRVKGRTW(TPO)L CGTPEYLAPE IILSKGYNKA VDWWALGVLI YEMAAGYP P FFADQPIQIY EKIVSGKVRF PSHFSSDLKD LLRNLLQVDL TKRFGNLKNG VNDIKNHKWF ATTDWIAIYQ RKVEAPFIP KFKGPGDTSN FDDYEEEEIR V(SEP)INEKCGKE FTEF

UniProtKB: cAMP-dependent protein kinase catalytic subunit alpha

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Macromolecule #2: cAMP-dependent protein kinase type I-alpha regulatory subunit

MacromoleculeName: cAMP-dependent protein kinase type I-alpha regulatory subunit
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Bos taurus (domestic cattle)
Molecular weightTheoretical: 47.458473 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MRGSHHHHHH GMASMTGGQQ MGRDLYDDDD KDPSSRSAAG TMASGTTASE EERSLRECEL YVQKHNIQAL LKDSIVQLCT ARPERPMAF LREYFEKLEK EEAKQIQNLQ KAGSRADSRE DEISPPPPNP VVKGRRRRGA ISAEVYTEED AASYVRKVIP K DYKTMAAL ...String:
MRGSHHHHHH GMASMTGGQQ MGRDLYDDDD KDPSSRSAAG TMASGTTASE EERSLRECEL YVQKHNIQAL LKDSIVQLCT ARPERPMAF LREYFEKLEK EEAKQIQNLQ KAGSRADSRE DEISPPPPNP VVKGRRRRGA ISAEVYTEED AASYVRKVIP K DYKTMAAL AKAIEKNVLF SHLDDNERSD IFDAMFPVSF IAGETVIQQG DEGDNFYVID QGEMDVYVNN EWATSVGEGG SF GELALIY GTPRAATVKA KTNVKLWGID RDSYRRILMG STLRKRKMYE EFLSKVSILE SLDKWERLTV ADALEPVQFE DGQ KIVVQG EPGDEFFIIL EGSAAVLQRR SENEEFVEVG RLGPSDYFGE IALLMNRPKA ATVVARGPLK CVKLDRPRFE RVLG PCSDI LKRNIQQYNS FVSLSVA

UniProtKB: cAMP-dependent protein kinase type I-alpha regulatory subunit

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Macromolecule #3: ADENOSINE-5'-TRIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 3 / Number of copies: 1 / Formula: ATP
Molecular weightTheoretical: 507.181 Da
Chemical component information

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.6 mg/mL
BufferpH: 7
Component:
ConcentrationFormulaName
50.0 mMMOPS3-(N-morpholino)propanesulfonic acid
50.0 mMNaClSodium Chloride
5.0 mMMgCl2Magnesium Chloride
0.1 mMATPAdenosine 5-Triphosphate
1.0 mMB-ME2-Mercaptoethanol
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Number real images: 4559 / Average electron dose: 49.66 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: OTHER / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 2683140
CTF correctionSoftware - Name: cryoSPARC (ver. 4.2) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 5.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.2) / Number images used: 9847
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE / Software - Name: cryoSPARC (ver. 4.2)
Final 3D classificationNumber classes: 3 / Software - Name: cryoSPARC (ver. 4.2)

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Atomic model buiding 1

Initial model
PDB IDChain

3fhi

source_name: PDB, initial_model_type: experimental model

2qcs

source_name: PDB, initial_model_type: experimental model
RefinementSpace: REAL / Protocol: RIGID BODY FIT / Overall B value: 388.81
Output model

PDB-9ede:
Reset Type-I Protein Kinase A Holoenzyme

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