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- PDB-7pid: Protein kinase A catalytic subunit in complex with PKI5-24 and EN060 -

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Basic information

Entry
Database: PDB / ID: 7pid
TitleProtein kinase A catalytic subunit in complex with PKI5-24 and EN060
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 / regulation of proteasomal protein catabolic process / negative regulation of TORC1 signaling / 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 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / mRNA processing / 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 / cytoplasm / cytosol
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-7QI / 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: 1.496 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 2.2Oct 23, 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
Water5,495305
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1970 Å2
ΔGint-17 kcal/mol
Surface area17190 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.703, 73.059, 109.498
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 / Organ: Ovary
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: PKI5-24, the last two residues are disordered / Source: (synth.) Mus musculus (house mouse) / References: UniProt: P63248
#3: Chemical ChemComp-7QI / 2-azanyl-5-[3-[(3R)-morpholin-3-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.: 305 / 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: 54.51 %
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: 1.496→45.7610803693 Å / Num. obs: 76966 / % possible obs: 99.6 % / Redundancy: 13.08 % / Biso Wilson estimate: 20.1617100127 Å2 / CC1/2: 0.999 / Rsym value: 0.053 / Net I/σ(I): 27.22
Reflection shellResolution: 1.496→1.58 Å / Redundancy: 13 % / Mean I/σ(I) obs: 5.86 / Num. unique obs: 12087 / CC1/2: 0.956 / Rsym value: 0.5 / % possible all: 97.8

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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: 1.496→45.7610803693 Å / SU ML: 0.089950383788 / Cross valid method: FREE R-VALUE / σ(F): 1.38082386903 / Phase error: 13.1228058308
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.161380451467 3849 5.0012993763 %
Rwork0.132396167393 73111 -
obs0.133838625045 76960 99.5859213251 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 29.4098029108 Å2
Refinement stepCycle: LAST / Resolution: 1.496→45.7610803693 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2968 0 29 305 3302
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.007816987107073225
X-RAY DIFFRACTIONf_angle_d0.9946433780274396
X-RAY DIFFRACTIONf_chiral_restr0.0793775541051463
X-RAY DIFFRACTIONf_plane_restr0.00676048261795584
X-RAY DIFFRACTIONf_dihedral_angle_d20.57297067361197
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.496-1.5110.2076322484421290.1318625607942450X-RAY DIFFRACTION90.8738548273
1.511-1.53090.1655113380371410.1032030946482674X-RAY DIFFRACTION99.8581057112
1.5309-1.55190.1729121823781410.105243550262684X-RAY DIFFRACTION99.9292536258
1.5519-1.57410.1507503438341410.09494870322672674X-RAY DIFFRACTION99.7166135317
1.5741-1.59760.1526074600131410.09356714309112666X-RAY DIFFRACTION99.8932384342
1.5976-1.62250.1626076137941420.09422915272312698X-RAY DIFFRACTION99.5094604064
1.6225-1.64910.1291670907011400.08788532758222672X-RAY DIFFRACTION99.8225062123
1.6491-1.67760.1562664076491420.08524062858882703X-RAY DIFFRACTION100
1.6776-1.70810.1373918824821420.08617867613022682X-RAY DIFFRACTION100
1.7081-1.74090.1258897315591410.08653468767972691X-RAY DIFFRACTION100
1.7409-1.77650.1419401350371430.08888924666412716X-RAY DIFFRACTION100
1.7765-1.81510.1257353984761400.09216440004492665X-RAY DIFFRACTION99.9643620813
1.8151-1.85730.1637664515391430.1044140723732701X-RAY DIFFRACTION100
1.8573-1.90380.1484490764631420.1091759821262702X-RAY DIFFRACTION99.9297259311
1.9038-1.95530.1494605513151430.1113246007572719X-RAY DIFFRACTION99.9650716032
1.9553-2.01280.1424669380651410.1141944897722684X-RAY DIFFRACTION100
2.0128-2.07780.1562071163291430.1171228966212719X-RAY DIFFRACTION100
2.0778-2.1520.1567869151531430.1226821461432720X-RAY DIFFRACTION100
2.152-2.23820.174744284861420.1229004132532695X-RAY DIFFRACTION99.8240675581
2.2382-2.340.1504033393751450.1244893287792744X-RAY DIFFRACTION100
2.34-2.46340.1478086903431420.1292497625632713X-RAY DIFFRACTION100
2.4634-2.61770.1684693306071450.1273057842922744X-RAY DIFFRACTION100
2.6177-2.81980.1570352349411450.1457199875732753X-RAY DIFFRACTION100
2.8198-3.10350.1479897457351440.1467290621552743X-RAY DIFFRACTION100
3.1035-3.55250.1728092801471460.1560590022042772X-RAY DIFFRACTION99.9315068493
3.5525-4.47510.1663255733511470.1364410013862792X-RAY DIFFRACTION99.6271186441
4.4751-45.76108036930.181346776431550.1646345379242935X-RAY DIFFRACTION99.935316947

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