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- PDB-5m6v: Cocrystal structure of cAMP-dependent Protein Kinase (PKA) in com... -

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Basic information

Entry
Database: PDB / ID: 5m6v
TitleCocrystal structure of cAMP-dependent Protein Kinase (PKA) in complex with a double methylated Fasudil-derivative
Components
  • cAMP-dependent protein kinase catalytic subunit alpha
  • cAMP-dependent protein kinase inhibitor alpha
KeywordsTRANSFERASE / PKA / Kinase / Fasudil-derivative / Inhibition / Cocrystal / 3x-Phosphorylated
Function / homology
Function and homology information


negative regulation of cAMP-dependent protein kinase activity / 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 cAMP-dependent protein kinase activity / 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 / 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. / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 ...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. / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-H52 / cAMP-dependent protein kinase catalytic subunit alpha / cAMP-dependent protein kinase inhibitor alpha
Similarity search - Component
Biological speciesCricetulus griseus (Chinese hamster)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.418 Å
AuthorsWienen-Schmidt, B. / Heine, A. / Klebe, G.
Funding support Belgium, 1items
OrganizationGrant numberCountry
European Research Council268145 - Project Acronym: DrugProfilBind Belgium
CitationJournal: To be Published
Title: Cocrystal structure of cAMP-dependent Protein Kinase (PKA) in complex with different Fasudil-derivatives
Authors: Wienen-Schmidt, B. / Jonker, H. / Gerber, H.-D. / Saxena, K. / Kudlinzki, D. / Sreeramulu, S. / Heine, A. / Schwalbe, H. / Klebe, G.
History
DepositionOct 26, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 6, 2018Provider: repository / Type: Initial release
Revision 1.1Jan 17, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)43,6603
Polymers43,3402
Non-polymers3191
Water7,873437
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2440 Å2
ΔGint2 kcal/mol
Surface area17110 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.537, 73.183, 108.847
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein cAMP-dependent protein kinase catalytic subunit alpha / PKA C-alpha


Mass: 41113.766 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Phosphorylated at Ser11, Thr198, Ser339 / Source: (gene. exp.) Cricetulus griseus (Chinese hamster) / Gene: PRKACA / Production host: Escherichia coli (E. coli) / 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 / Fragment: UNP residues 6-25 / Source method: obtained synthetically
Details: Amino acids 5-24 from cAMP-dependent protein kinase inhibitor alpha from Sigma (order ID: P7739)
Source: (synth.) Homo sapiens (human) / References: UniProt: P61925
#3: Chemical ChemComp-H52 / (S)-2-METHYL-1-[(4-METHYL-5-ISOQUINOLINE)SULFONYL]-HOMOPIPERAZINE


Mass: 319.422 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H21N3O2S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 437 / Source method: isolated from a natural source / Formula: H2O
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: 2.15 Å3/Da / Density % sol: 54.27 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop / pH: 6.9
Details: Drop: 10 mg/ml PKA (0.240 mM) 30 mM MBT (MES/Bis-Tris Puffer pH 6.9) 1 mM DTT 0.1 mM EDTA 75 mM LiCl 0.03 mM Mega 8 0.07mM PKI (Sigma: P7739) 1.2 mM ligand solved in DMSO (50 mM Stock) ...Details: Drop: 10 mg/ml PKA (0.240 mM) 30 mM MBT (MES/Bis-Tris Puffer pH 6.9) 1 mM DTT 0.1 mM EDTA 75 mM LiCl 0.03 mM Mega 8 0.07mM PKI (Sigma: P7739) 1.2 mM ligand solved in DMSO (50 mM Stock) Reservoir: 18% Methanol 0.003 mL drop volume, 0.4 mL reservoir volume

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: BM14 / Wavelength: 0.97625 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Apr 13, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 1.418→45.713 Å / Num. obs: 88220 / % possible obs: 98.9 % / Redundancy: 7.284 % / Rsym value: 0.045 / Net I/σ(I): 23.58
Reflection shellResolution: 1.42→1.5 Å / Redundancy: 7.287 % / Rmerge(I) obs: 0.476 / Mean I/σ(I) obs: 3.86 / % possible all: 97.1

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155: ???)refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1Q8W

1q8w


Resolution: 1.418→31.028 Å / SU ML: 0.12 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 14.76
RfactorNum. reflection% reflection
Rfree0.174 4410 5 %
Rwork0.1435 --
obs0.145 88218 98.82 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.418→31.028 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3000 0 22 437 3459
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0083259
X-RAY DIFFRACTIONf_angle_d1.0344437
X-RAY DIFFRACTIONf_dihedral_angle_d20.6971219
X-RAY DIFFRACTIONf_chiral_restr0.073463
X-RAY DIFFRACTIONf_plane_restr0.007606
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.4177-1.43380.23921360.18862588X-RAY DIFFRACTION93
1.4338-1.45070.20011440.16412741X-RAY DIFFRACTION98
1.4507-1.46840.19211450.15962751X-RAY DIFFRACTION98
1.4684-1.4870.1971440.15012736X-RAY DIFFRACTION98
1.487-1.50660.15891450.13862762X-RAY DIFFRACTION99
1.5066-1.52720.19411430.13872722X-RAY DIFFRACTION98
1.5272-1.5490.19011440.13832732X-RAY DIFFRACTION99
1.549-1.57210.18361470.13422788X-RAY DIFFRACTION99
1.5721-1.59670.16591450.13142762X-RAY DIFFRACTION98
1.5967-1.62290.19551450.12832758X-RAY DIFFRACTION99
1.6229-1.65090.17341460.12812765X-RAY DIFFRACTION99
1.6509-1.68090.18551460.12672777X-RAY DIFFRACTION99
1.6809-1.71320.16621450.12572756X-RAY DIFFRACTION99
1.7132-1.74820.15941460.12982766X-RAY DIFFRACTION99
1.7482-1.78620.17481460.12752775X-RAY DIFFRACTION99
1.7862-1.82770.17351480.13152822X-RAY DIFFRACTION99
1.8277-1.87340.17511470.13622792X-RAY DIFFRACTION99
1.8734-1.92410.16441460.14332769X-RAY DIFFRACTION99
1.9241-1.98070.21321480.14662806X-RAY DIFFRACTION99
1.9807-2.04460.1911480.14622813X-RAY DIFFRACTION99
2.0446-2.11770.19011470.14692802X-RAY DIFFRACTION100
2.1177-2.20240.1681480.14132810X-RAY DIFFRACTION100
2.2024-2.30260.16811490.13322830X-RAY DIFFRACTION99
2.3026-2.4240.14351500.13692842X-RAY DIFFRACTION100
2.424-2.57580.17751490.13732827X-RAY DIFFRACTION100
2.5758-2.77460.15911500.15232851X-RAY DIFFRACTION100
2.7746-3.05360.19321510.15612870X-RAY DIFFRACTION100
3.0536-3.49490.18411510.1572877X-RAY DIFFRACTION100
3.4949-4.40120.15961530.13882910X-RAY DIFFRACTION100
4.4012-31.03550.16221580.14863008X-RAY DIFFRACTION98

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