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- PDB-7pie: Protein kinase A catalytic subunit in complex with PKI5-24 and EN068 -

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Basic information

Entry
Database: PDB / ID: 7pie
TitleProtein kinase A catalytic subunit in complex with PKI5-24 and EN068
Components
  • cAMP-dependent protein kinase catalytic subunit alpha
  • cAMP-dependent protein kinase inhibitor alpha
KeywordsTRANSFERASE / Protein Kinase / Ligand complex
Function / homology
Function and homology information


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 / negative regulation of protein import into nucleus ...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 / 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 / ciliary base / protein kinase A regulatory subunit binding / protein kinase A catalytic subunit binding / intracellular potassium ion homeostasis / mesoderm formation / plasma membrane raft / axoneme / sperm flagellum / postsynaptic modulation of chemical synaptic transmission / regulation of G2/M transition of mitotic cell cycle / negative regulation of TORC1 signaling / regulation of proteasomal protein catabolic process / positive regulation of gluconeogenesis / protein serine/threonine/tyrosine kinase activity / cellular response to glucagon stimulus / acrosomal vesicle / protein export from nucleus / positive regulation of phagocytosis / positive regulation of protein export from nucleus / negative regulation of smoothened signaling pathway / neural tube closure / neuromuscular junction / cellular response to glucose stimulus / positive regulation of cholesterol biosynthetic process / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / positive regulation of insulin secretion / mRNA processing / adenylate cyclase-activating G protein-coupled receptor signaling pathway / manganese ion binding / cellular response to heat / postsynapse / regulation of cell cycle / nuclear speck / protein domain specific binding / protein serine kinase activity / protein serine/threonine kinase activity / ubiquitin protein ligase binding / centrosome / protein kinase binding / perinuclear region of cytoplasm / glutamatergic synapse / magnesium ion binding / negative regulation of transcription by RNA polymerase II / mitochondrion / ATP binding / nucleus / cytosol / cytoplasm
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. / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. ...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. / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-7QF / cAMP-dependent protein kinase catalytic subunit alpha / cAMP-dependent protein kinase inhibitor alpha
Similarity search - Component
Biological speciesCricetulus griseus (Chinese hamster)
Mus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.427 Å
AuthorsGlinca, S. / Mueller, J.M. / Ruf, M. / Merkl, S.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2022
Title: Magnet for the Needle in Haystack: "Crystal Structure First" Fragment Hits Unlock Active Chemical Matter Using Targeted Exploration of Vast Chemical Spaces.
Authors: Muller, J. / Klein, R. / Tarkhanova, O. / Gryniukova, A. / Borysko, P. / Merkl, S. / Ruf, M. / Neumann, A. / Gastreich, M. / Moroz, Y.S. / Klebe, G. / Glinca, S.
History
DepositionAug 19, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 21, 2022Provider: repository / Type: Initial release
Revision 1.1Dec 21, 2022Group: 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 2.0May 24, 2023Group: Non-polymer description / Category: chem_comp / Item: _chem_comp.formula
Revision 2.1Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 2.2Nov 20, 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

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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)43,8184
Polymers43,4202
Non-polymers3982
Water5,837324
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1960 Å2
ΔGint-17 kcal/mol
Surface area17150 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.764, 73.006, 109.486
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: 41193.746 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Cricetulus griseus (Chinese hamster) / Gene: PRKACA
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: P25321, 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.: 1 / Source method: obtained synthetically / Details: PKI 5-24, the last 2 residues are disordered / Source: (synth.) Mus musculus (house mouse) / References: UniProt: P63248
#3: Chemical ChemComp-7QF / 2-azanyl-5-[3-[(2R)-morpholin-2-yl]phenyl]benzenecarbonitrile


Mass: 279.336 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H17N3O / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-MPD / (4S)-2-METHYL-2,4-PENTANEDIOL


Mass: 118.174 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14O2 / Comment: precipitant*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 324 / 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: 2.7 Å3/Da / Density % sol: 54.52 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop
Details: Protein at 8 mg/mL in 100 mM Mes-Bis-Tris pH 6.9, 75 mM Lithium chloride, 1 mM DTT, 100 mM Sodium-EDTA. Master-Mix: 540 uL of protein + 15 uL 10 mM Mega8 in Water + 45 uL 10 mM PKI5-24 in ...Details: Protein at 8 mg/mL in 100 mM Mes-Bis-Tris pH 6.9, 75 mM Lithium chloride, 1 mM DTT, 100 mM Sodium-EDTA. Master-Mix: 540 uL of protein + 15 uL 10 mM Mega8 in Water + 45 uL 10 mM PKI5-24 in protein-buffer. 70 % Master-Mix mixed with 30 % 50 mM ligand in DMSO before setting of drops. 15-24 % Methanol/Water in Reservoir.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, DESY / Beamline: P11 / Wavelength: 1.033193 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Apr 21, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.033193 Å / Relative weight: 1
ReflectionResolution: 1.427→45.7769014348 Å / Num. obs: 88126 / % possible obs: 99.7 % / Redundancy: 13.14 % / Biso Wilson estimate: 19.3147213148 Å2 / CC1/2: 0.999 / Rsym value: 0.047 / Net I/σ(I): 28.94
Reflection shellResolution: 1.427→1.51 Å / Redundancy: 13.36 % / Mean I/σ(I) obs: 5.47 / Num. unique obs: 14074 / CC1/2: 0.958 / Rsym value: 0.5 / % possible all: 99.6

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Processing

Software
NameVersionClassification
PHENIX1.10.1_2155refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5M6Y

5m6y


Resolution: 1.427→45.7769014348 Å / SU ML: 0.0784601912234 / Cross valid method: FREE R-VALUE / σ(F): 1.37252447037 / Phase error: 12.7024639086
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.157911223999 4407 5.0009645609 %
Rwork0.13568506166 83716 -
obs0.136797965222 88123 99.6584676279 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 28.8305837838 Å2
Refinement stepCycle: LAST / Resolution: 1.427→45.7769014348 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2927 0 29 324 3280
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0103676024863170
X-RAY DIFFRACTIONf_angle_d1.090248788834323
X-RAY DIFFRACTIONf_chiral_restr0.0807391823168459
X-RAY DIFFRACTIONf_plane_restr0.00813146064545573
X-RAY DIFFRACTIONf_dihedral_angle_d19.03381783021162
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.427-1.44190.1734405120591440.1408690228322724X-RAY DIFFRACTION98.6244841816
1.4419-1.45890.1781623211311450.1172100964122757X-RAY DIFFRACTION99.828001376
1.4589-1.47670.1443834191831440.1123407088842738X-RAY DIFFRACTION99.8268098372
1.4767-1.49530.1604793634541460.1059332910632772X-RAY DIFFRACTION99.8289428669
1.4953-1.5150.1591437195261450.1016842728412768X-RAY DIFFRACTION99.7944501542
1.515-1.53580.1494751033871460.09804644439912775X-RAY DIFFRACTION99.7950119576
1.5358-1.55770.1573475952161450.09902974357012745X-RAY DIFFRACTION99.68954812
1.5577-1.5810.1243474697621440.09287629869612735X-RAY DIFFRACTION99.5504840941
1.581-1.60570.1327798864331460.09021833892382770X-RAY DIFFRACTION99.4203886805
1.6057-1.6320.1325844502421450.09057784010332766X-RAY DIFFRACTION98.8455008489
1.632-1.66010.1304410982651430.09325231115982712X-RAY DIFFRACTION98.3804272915
1.6601-1.69030.141700800591460.09227649144972779X-RAY DIFFRACTION100
1.6903-1.72280.1449362815311460.0958266462812763X-RAY DIFFRACTION100
1.7228-1.7580.1511065976491460.09937779411442788X-RAY DIFFRACTION100
1.758-1.79620.1416789355641470.09938839480812780X-RAY DIFFRACTION100
1.7962-1.8380.1585371665921470.105505816142799X-RAY DIFFRACTION99.8305659099
1.838-1.8840.1495556798441460.1142608895132767X-RAY DIFFRACTION100
1.884-1.93490.1537063519871470.1126401706962792X-RAY DIFFRACTION99.9659863946
1.9349-1.99190.1464188139851460.1142345925362787X-RAY DIFFRACTION100
1.9919-2.05620.1320184740811480.1194305030842811X-RAY DIFFRACTION100
2.0562-2.12970.1513637073741470.1220660728122781X-RAY DIFFRACTION99.659632403
2.1297-2.21490.1639595395291460.1244983086592784X-RAY DIFFRACTION99.2211310532
2.2149-2.31570.1540332861771460.1206297515472762X-RAY DIFFRACTION98.9452194624
2.3157-2.43780.1419472272021490.1271347102732848X-RAY DIFFRACTION100
2.4378-2.59050.1677443120651480.1308117200052810X-RAY DIFFRACTION100
2.5905-2.79050.1530535205461480.1427126038722814X-RAY DIFFRACTION99.8988195616
2.7905-3.07130.1697856066481500.1534331746672843X-RAY DIFFRACTION100
3.0713-3.51560.1642151050911500.159005562882852X-RAY DIFFRACTION99.8005319149
3.5156-4.42870.1602134053421510.1445893993452864X-RAY DIFFRACTION99.0147783251
4.4287-45.77690143480.1740124216261600.1742030738763030X-RAY DIFFRACTION99.8747651847

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