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- PDB-5m0b: Cocrystal structure of cAMP-dependent Protein Kinase (PKA) in com... -

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Basic information

Entry
Database: PDB / ID: 5m0b
TitleCocrystal structure of cAMP-dependent Protein Kinase (PKA) in complex with a short-chained N-(2-aminoethyl)isoquinoline-5-sulfonamide) Fasudil-derivative (Ligand 03)
Components(cAMP-dependent protein kinase ...) x 2
KeywordsTRANSFERASE / PKA / Kinase / Fasudil-derivative / Inhibition / Cocrystal / 3x-Phosphorylated / Ligand 03
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 / cellular response to cold / regulation of osteoblast differentiation / sperm capacitation / ciliary base / negative regulation of glycolytic process through fructose-6-phosphate / protein kinase A regulatory subunit binding / protein kinase A catalytic subunit binding / mesoderm formation / sperm flagellum / plasma membrane raft / axoneme / 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 / protein export from nucleus / acrosomal vesicle / positive regulation of protein export from nucleus / negative regulation of smoothened signaling pathway / neural tube closure / positive regulation of cholesterol biosynthetic process / cellular response to glucose stimulus / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / neuromuscular junction / 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 / centrosome / ubiquitin protein ligase binding / protein kinase binding / perinuclear region of cytoplasm / glutamatergic synapse / negative regulation of transcription by RNA polymerase II / magnesium ion binding / 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. / 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
N-(2-AMINOETHYL)ISOQUINOLINE-5-SULFONAMIDE / METHANOL / 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: 1.506 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.R.A. / Gerber, H.-D. / Saxena, K. / Kudlinzki, D. / Sreeramulu, S. / Heine, A. / Schwalbe, H. / Klebe, G.
History
DepositionOct 4, 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 1.2Oct 16, 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)43,7746
Polymers43,3402
Non-polymers4344
Water9,098505
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3000 Å2
ΔGint-11 kcal/mol
Surface area16770 Å2
MethodPISA
Unit cell
Length a, b, c (Å)57.945, 71.736, 109.922
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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CAMP-dependent protein kinase ... , 2 types, 2 molecules AB

#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 / Source method: obtained synthetically
Details: Amino acids 5-24 from cAMP-dependent protein kinase inhibitor alpha from Sigma (order ID: P7739); the last amino acid is not well defined in the crystal structure
Source: (synth.) Homo sapiens (human) / References: UniProt: P61925

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Non-polymers , 4 types, 509 molecules

#3: Chemical ChemComp-IQU / N-(2-AMINOETHYL)ISOQUINOLINE-5-SULFONAMIDE


Mass: 251.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H13N3O2S
#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: Chemical ChemComp-MOH / METHANOL


Mass: 32.042 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: CH4O
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 505 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.18 Å3/Da / Density % sol: 53.33 %
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: 1.506→45.08 Å / Num. obs: 73047 / % possible obs: 99.9 % / Redundancy: 7.32 % / Rsym value: 0.054 / Net I/σ(I): 26.28
Reflection shellResolution: 1.506→1.6 Å / Redundancy: 7.26 % / Rmerge(I) obs: 0.498 / Mean I/σ(I) obs: 3.89 / % possible all: 99.7

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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: 1.506→39.876 Å / SU ML: 0.12 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 14.18
RfactorNum. reflection% reflection
Rfree0.1594 3652 5 %
Rwork0.132 --
obs0.1334 73039 99.87 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.506→39.876 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2992 0 29 505 3526
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0083161
X-RAY DIFFRACTIONf_angle_d0.9554287
X-RAY DIFFRACTIONf_dihedral_angle_d15.4041874
X-RAY DIFFRACTIONf_chiral_restr0.062452
X-RAY DIFFRACTIONf_plane_restr0.007565
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.5063-1.52620.26991380.17432615X-RAY DIFFRACTION99
1.5262-1.54710.18841370.15572613X-RAY DIFFRACTION100
1.5471-1.56920.21581390.14582643X-RAY DIFFRACTION100
1.5692-1.59260.18941400.13732655X-RAY DIFFRACTION100
1.5926-1.61750.21351380.15122607X-RAY DIFFRACTION99
1.6175-1.6440.20961390.15312639X-RAY DIFFRACTION100
1.644-1.67230.18291380.12492629X-RAY DIFFRACTION100
1.6723-1.70270.15771400.12192671X-RAY DIFFRACTION100
1.7027-1.73550.17471370.11642596X-RAY DIFFRACTION100
1.7355-1.77090.15931410.11232677X-RAY DIFFRACTION100
1.7709-1.80940.1591390.11192647X-RAY DIFFRACTION100
1.8094-1.85150.16691390.11812631X-RAY DIFFRACTION100
1.8515-1.89780.14971400.11912660X-RAY DIFFRACTION100
1.8978-1.94910.17211390.12222644X-RAY DIFFRACTION100
1.9491-2.00650.14851410.12552689X-RAY DIFFRACTION100
2.0065-2.07120.15571400.12812650X-RAY DIFFRACTION100
2.0712-2.14530.151410.12112678X-RAY DIFFRACTION100
2.1453-2.23120.1461400.11612657X-RAY DIFFRACTION100
2.2312-2.33270.15751400.11892659X-RAY DIFFRACTION100
2.3327-2.45570.15071400.12492670X-RAY DIFFRACTION100
2.4557-2.60950.14951420.12682697X-RAY DIFFRACTION100
2.6095-2.81090.15421420.13822701X-RAY DIFFRACTION100
2.8109-3.09370.15121420.13942693X-RAY DIFFRACTION100
3.0937-3.54110.14111440.14122735X-RAY DIFFRACTION100
3.5411-4.46050.14261450.12872759X-RAY DIFFRACTION100
4.4605-39.89050.17091510.15112872X-RAY DIFFRACTION100

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